Ethinyl Estradiol

Third quarter 2025 revenue of $1.602 billion, up 1% as-reported and down 1% excluding the impact of foreign currency Third quarter 2025 diluted earnings per share of $0.61 and non-GAAP Adjusted diluted earnings per share of $1.01 Third quarter 2025 net income of $160 million and Adjusted EBITDA (non-GAAP) of $518 million, representing an Adjusted EBITDA margin of 32.3% Revenue guidance range for full year 2025 lowered to $6.200 billion to $6.250 billion; Adjusted EBITDA margin guidance lowered to ~31.0% JERSEY CITY, N.J.--(BUSINESS WIRE)--Organon (NYSE: OGN) today announced its results for the third quarter ended September 30, 2025. “I am humbled to be working alongside our talented team during this pivotal time for Organon,” said Joe Morrissey, Organon’s Interim Chief Executive Officer. “We are harnessing the company's many strengths, including a diverse portfolio that we expect will generate more than $900 million in free cash flow before one-time costs this year. We also remain committed to exercising cost discipline and reducing our debt burden proactively, where possible. These actions will create additional balance sheet capacity, positioning us to pursue future growth opportunities in women’s health and further our mission to deliver impactful medicines and solutions for a healthier every day.” Third Quarter 2025 Revenue in $ millions Q3 2025 Q3 2024 VPY VPY ex-FX Women’s Health $ 429 $ 440 (3)% (4)% General Medicines Biosimilars 196 165 19% 19% Established Brands 956 951 1% (3)% Other (1) 21 26 (15)% (18)% Revenue $ 1,602 $ 1,582 1% (1)% Totals may not foot due to rounding and percentages are computed using unrounded amounts. (1) Other includes manufacturing sales to third parties. For the third quarter of 2025, total revenue was $1.602 billion, up 1% on an as-reported basis and down 1% excluding the impact of foreign currency (ex-FX), compared with the third quarter of 2024. Women’s Health revenue declined 3% as-reported and declined 4% ex-FX in the third quarter of 2025, compared with the third quarter of 2024. Sales of Nexplanon® (etonogestrel implant) decreased 9% ex-FX in the quarter compared with the prior year period primarily due to lower demand in the United States primarily driven by decreased funding of government programs, partially offset by increased demand in Brazil and the timing of tenders, primarily in Mexico. Third quarter Nexplanon performance was partially offset with 5% ex-FX growth in NuvaRing® (etonogestrel / ethinyl estradiol vaginal ring), 4% ex-FX growth in MarvelonTM (desogestrel and ethinyl estradiol pill) and MercilonTM (desogestrel and ethinyl estradiol pill), as well as a 29% ex-FX increase in Jada® system. *Estimated net impact from pull-forward Nexplanon revenue associated with the company's sales practices for wholesalers in the U.S. as referenced in the company’s Current Report on Form 8-K, filed with the SEC on October 27, 2025, was approximately $2 million during the third quarter ended September 30, 2025. The company has ceased these sales practices for wholesalers. Biosimilars revenue increased 19% on both an as-reported basis and ex-FX in the third quarter of 2025, compared with the third quarter of 2024, primarily due to strong performance of Hadlima® (adalimumab-bwwd) and the favorable timing of an international tender for Ontruzant® (trastuzumab-dttb). To a lesser extent, during the third quarter the Biosimilars portfolio also benefitted from contribution from new assets; Bildyos® (denosumab-nxxp) and Bilprevda® (denosumab-nxxp), which was approved by the FDA in September 2025, and Tofidence® (tocilizumab-bavi), which the company acquired in the second quarter of 2025. Established Brands revenue increased 1% as-reported and declined 3% ex-FX in the third quarter of 2025. Revenue contribution of Emgality®(1) (galcanezumab-gnlm) and Vtama®(2) (tapinarof) partially offset the impact of the loss of exclusivity (“LOE”) of Atozet™ (ezetimibe and atorvastatin) in key markets in Europe as well as declines in the respiratory portfolio. Performance in the respiratory portfolio was primarily driven by an approximate 40% ex-FX decline in Singulair® (montelukast sodium), due to lower demand outside of the United States and the negative impact from price reductions in Japan and China as well as performance of Dulera® (formoterol and fumarate dihydrate), which declined 30% ex-FX primarily due to the loss of a customer contract in the first part of the year, combined with increased discount rate pressure in the United States, as well as supply constraints. (1) Organon acquired certain European licensing and distribution rights to Emgality and Rayvow from Eli Lilly and Company (“Eli Lilly”) beginning in early 2024. Emgality and Rayvow are registered trademarks of Eli Lilly in the European Union and other countries (used under license). (2) Vtama was acquired as part of Organon's acquisition of Dermavant Sciences Ltd. (“Dermavant”), which closed on October 28, 2024. Third Quarter 2025 Profitability in $ millions, except per share amounts Q3 2025 Q3 2024 VPY Revenues $ 1,602 $ 1,582 1% Cost of sales 745 659 13% Gross profit 857 923 (7)% Non-GAAP Adjusted gross profit (1) 966 976 (1)% Net income 160 359 (55)% Non-GAAP Adjusted net income (1) 263 226 16% Diluted Earnings per Share (EPS) 0.61 1.38 (56)% Non-GAAP Adjusted diluted EPS (1) 1.01 0.87 16% Acquired in-process research & development (IPR&D) and milestones — 51 —% Adjusted EBITDA (Non-GAAP) (1, 2) 518 459 13% Q3 2025 Q3 2024 Gross margin 53.5 % 58.3 % Non-GAAP Adjusted gross margin (1) 60.3 % 61.7 % Adjusted EBITDA margin (Non-GAAP) (1, 2) 32.3 % 29.0 % (1) See Tables 4 and 5 for reconciliations of GAAP to non-GAAP financial measures. (2) Adjusted EBITDA and Adjusted EBITDA margin for Q3 2024 includes $51 million, related to acquired IPR&D and milestones. Reported gross margin in the third quarter of 2025 was 53.5% compared with 58.3% in the prior year period. One-time costs associated with optimizing the company’s manufacturing and supply network was the most significant driver in the year-over-year decline in reported gross margin. Non-GAAP Adjusted gross margin was 60.3% in the third quarter of 2025, compared to 61.7% in the third quarter of 2024. Unfavorable foreign exchange in inventory turns, pricing pressure and product mix were drivers in the decline of both reported gross margin and non-GAAP Adjusted gross margin. Net income for the third quarter of 2025 was $160 million, or $0.61 per diluted share, compared with $359 million, or $1.38 per diluted share, in the third quarter of 2024. For the third quarter of 2025, non-GAAP Adjusted net income was $263 million, or $1.01 per diluted share, compared with $226 million, or $0.87 per diluted share, in 2024. Non-GAAP Adjusted EBITDA margin was 32.3% in the third quarter of 2025 compared with 29.0% in the third quarter of 2024. The year-over-year improvement in Adjusted EBITDA margin was primarily driven by a 14% reduction in non-GAAP operating expenses. Capital Allocation Today, Organon’s Board of Directors declared a quarterly dividend of $0.02 for each issued and outstanding share of the company's common stock. The dividend is payable on December 11, 2025, to stockholders of record at the close of business on November 20, 2025. As of September 30, 2025, cash and cash equivalents were $672 million, and debt was $8.83 billion. Full Year Guidance Organon does not provide GAAP financial measures on a forward-looking basis because the company cannot predict with reasonable certainty and without unreasonable effort, the ultimate outcome of legal proceedings, unusual gains and losses, the occurrence of matters creating GAAP tax impacts, and acquisition-related expenses. These items are uncertain, depend on various factors, and could be material to Organon’s results computed in accordance with GAAP. Full year 2025 financial guidance is presented below on a non-GAAP basis, except revenue. Previous Guidance as of August 5, 2025 Current Guidance Revenue $6.275B - $6.375B $6.200B - $6.250B Nominal revenue growth (2.0%) - (0.4%) (3.2%) - (2.4%) FX translation impact ~$50M headwind ~ $35M - $45M tailwind Ex-FX revenue growth (1.2%) - 0.3% (3.7%) - (3.1%) Adjusted gross margin 60.0%-61.0% Unchanged SG&A Mid 20% range Unchanged R&D Upper single-digit Unchanged IPR&D* $6 million Unchanged Adjusted EBITDA margin (Non-GAAP) 31.0%-32.0% ~31.0% Interest ~$510M Unchanged Depreciation ~$135M Unchanged Effective non-GAAP tax rate 22.5%-24.5% Unchanged Fully diluted weighted average shares outstanding ~263M Unchanged *The company does not provide guidance for forward-looking IPR&D and milestone expense. The $6 million of forecasted IPR&D expense reflects IPR&D expense recorded through September 30, 2025. Webcast Information Organon will host a conference call at 8:30 a.m. Eastern Time today to discuss its third quarter financial results. To listen to the event and view the presentation slides via webcast, join from the Organon Investor Relations website at https://www.organon.com/investor-relations/events-and-presentations/. A replay of the webcast will be available approximately two hours after the conclusion of the live event on the company’s website. Institutional investors and analysts interested in participating in the call may join by dialing (888) 596-4144 (U.S. and Canada Toll-Free) or (646) 968-2525 and using the access code Conference ID: 1036555#. About Organon Organon (NYSE: OGN) is a global healthcare company with a mission to deliver impactful medicines and solutions for a healthier every day. With a portfolio of over 70 products across Women’s Health and General Medicines, which includes biosimilars, Organon focuses on addressing health needs that uniquely, disproportionately or differently affect women, while expanding access to essential treatments in over 140 markets. Headquartered in Jersey City, New Jersey, Organon is committed to advancing access, affordability, and innovation in healthcare. Learn more at http://www.organon.com and follow us on LinkedIn, Instagram, X, YouTube, TikTok and Facebook. Cautionary Note Regarding Non-GAAP Financial Measures This press release contains “non-GAAP financial measures,” which are financial measures that either exclude or include amounts that are correspondingly not excluded or included in the most directly comparable measures calculated and presented in accordance with U.S. generally accepted accounting principles (“GAAP”). Specifically, the company makes use of the non-GAAP financial measures Adjusted EBITDA, Adjusted EBITDA margin, Adjusted gross margin, Adjusted gross profit, Adjusted net income, and Adjusted diluted EPS, which are not recognized terms under GAAP and are presented only as a supplement to the company’s GAAP financial statements. This press release also provides certain measures that exclude the impact of foreign exchange. We calculate foreign exchange by converting our current-period local currency financial results using the prior period average currency rates and comparing these adjusted amounts to our current-period results. The company believes that these non-GAAP financial measures help to enhance an understanding of the company’s financial performance. However, the presentation of these measures has limitations as an analytical tool and should not be considered in isolation, or as a substitute for the company’s results as reported under GAAP. Because not all companies use identical calculations, the presentations of these non-GAAP measures may not be comparable to other similarly titled measures of other companies. Please refer to Table 4 and Table 5 of this press release for additional information, including relevant definitions and reconciliations of non-GAAP financial measures contained herein to the most directly comparable GAAP measures. In addition, the company’s full-year 2025 guidance measures (other than revenue) are provided on a non-GAAP basis because the company is unable to reasonably predict certain items contained in the GAAP measures. Such items include, but are not limited to, acquisition-related expenses, restructuring and related expenses, stock-based compensation, the ultimate outcome of legal proceedings, unusual gains and losses, the occurrence of matters creating GAAP tax impacts and other items not reflective of the company's ongoing operations. The company’s management uses the non-GAAP financial measures described above to evaluate the company’s performance and to guide operational and financial decision making. Further, the company’s management believes that these non-GAAP financial measures, which exclude certain items, help to enhance its ability to meaningfully communicate its underlying business performance, financial condition and results of operations. Cautionary Note Regarding Forward-Looking Statements Except for historical information, this press release includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995, including, but not limited to, statements about management’s expectations about Organon’s full-year 2025 guidance estimates and predictions regarding other financial information and metrics, as well as expectations regarding Organon’s franchise and product performance and strategy expectations for future periods. Forward-looking statements may be identified by words such as “guidance,” “potential,” “should,” “will,” “continue,” “expects,” “believes,” “future,” “estimates,” “opportunity,” or words of similar meaning. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. If underlying assumptions prove inaccurate, or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements. Risks and uncertainties include, but are not limited to, expanded brand and class competition in the markets in which Organon operates; trade protection measures and import or export licensing requirements, including the direct and indirect impacts of tariffs (including any potential pharmaceutical sector tariffs), trade sanctions or similar restrictions by the United States or other governments; changes in U.S. and foreign federal, state and local governmental funding allocations including the timing and amounts allocated to Organon’s customers and business partners; economic factors over which Organon has no control, including changes in inflation, interest rates, recessionary pressures, and foreign currency exchange rates; uncertainties surrounding the Audit Committee investigation described in Organon’s Current Report on Form 8-K, filed with the U.S. Securities and Exchange Commission (the “SEC”) on October 27, 2025 (the “Form 8-K”); the impact of litigation, regulatory investigations and inquiries, and other legal matters, including risks to Organon’s reputation and relationships with customers, wholesalers, suppliers, and other business partners; risks related to potential disruptions to Organon’s business as a result of the leadership changes announced in the Form 8-K, including the risk that appointing a new Chief Executive Officer may take longer than anticipated; Organon’s ability to remediate the material weaknesses in internal control over financial reporting and the related costs and management resources in connection therewith, as well as its ability to maintain effective controls over financial reporting and disclosure controls and procedures in the future; Organon’s ability to access the public securities and other capital and credit markets in accordance with its financial plans, the cost of such capital and overall condition of the capital and credit markets; actions that may be taken by credit rating agencies that could negatively affect either Organon’s access to or terms of financing or its financial condition and liquidity; Organon’s ability to meet its revenue and growth expectations and outlook; unfavorable publicity and media reports; the potential impact that actions by activist stockholders could have on the pursuit of our business strategies; the loss of key personnel or highly skilled employees; market volatility, downgrades to the U.S. government’s sovereign credit rating or its perceived creditworthiness, changing political or geopolitical conditions, market contraction, boycotts, and sanctions, as well as Organon’s ability to successfully manage uncertainties related to the foregoing; difficulties with performance of third parties Organon relies on for its business growth; the failure of any supplier to provide substances, materials, or services as agreed, or otherwise meet their obligations to us; the increased cost of supply, manufacturing, packaging, and operations; difficulties developing and sustaining relationships with commercial counterparties; competition from generic products as Organon’s products lose patent protection; any failure by Organon to retain market exclusivity for Nexplanon® (etonogestrel implant) or to obtain an additional period of exclusivity in the United States for Nexplanon subsequent to the expiration of the rod patents in 2027; the continued impact of the September 2024 LOE for Atozet™ (ezetimibe and atorvastatin); the success of our efforts to adapt our business and sales strategies to address the changing market and regulatory landscape in order to achieve our business objectives and remain “competitive;” restructurings or other disruptions at the U.S. Food and Drug Administration (“FDA”), the SEC and other U.S. and comparable government agencies; difficulties and uncertainties inherent in the implementation of Organon’s acquisition strategy or failure to recognize the benefits of such acquisitions; pricing pressures globally, including rules and practices of managed care groups, judicial decisions and governmental laws and regulations related to or affecting Medicare, Medicaid and health care reform, pharmaceutical pricing and reimbursement, access to our products, international reference pricing, including Most-Favored-Nation drug pricing, and other pricing-related initiatives and policy efforts; the impact of higher selling and promotional costs; changes in government laws and regulations in the United States and other jurisdictions, including laws and regulations governing the research, development, approval, clearance, manufacturing, supply, distribution, and/or marketing of our products and related intellectual property, environmental regulations, and the enforcement thereof affecting Organon’s business; efficacy, safety or other quality concerns with respect to our marketed products, whether or not scientifically justified, leading to product recalls, withdrawals, labeling changes, or declining sales; delays or failures to demonstrate adequate efficacy and safety of Organon’s product candidates in pre-clinical and clinical trials, which may prevent or delay the development, approval, clearance, or commercialization of Organon’s product candidates; future actions of third parties, including significant changes in customer relationships or changes in the behavior and spending patterns of purchasers of health care products and services, including delaying medical procedures, rationing prescription medications, reducing the frequency of physician visits and forgoing health care insurance coverage; legal factors, including product liability claims, antitrust litigation and governmental investigations, including tax disputes, environmental claims and patent disputes with branded and generic competitors, any of which could preclude commercialization of products or negatively affect the profitability of existing products; lost market opportunity resulting from delays and uncertainties in clinical trials and the approval or clearance process of the FDA and other regulatory authorities; the failure by Organon or its third party collaborators and/or their suppliers to fulfill our or their regulatory or quality obligations, which could lead to a delay in regulatory approval or commercial marketing of Organon’s products; cyberattacks on, or other failures, accidents, or security breaches of, Organon’s or third-party providers’ information technology systems, which could disrupt Organon’s operations and those of third parties upon which it relies; increased focus on privacy issues in countries around the world, including the United States, the European Union, and China, and a more difficult legislative and regulatory landscape for privacy and data protection that continues to evolve with the potential to directly affect Organon’s business, including recently enacted laws in a majority of states in the United States requiring security breach notification; changes in tax laws including changes related to the taxation of foreign earnings; the impact of any future pandemic, epidemic, or similar public health threat on Organon’s business, operations and financial performance; loss of key employees or inability to identify and recruit new employees; changes in accounting pronouncements promulgated by standard-setting or regulatory bodies, including the Financial Accounting Standards Board and the SEC, that are adverse to Organon; and volatility of commodity prices, fuel, shipping rates that impact the costs and/or ability to supply Organon’s products. The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s filings with the SEC, including the company’s most recent Annual Report on Form 10-K (as amended), Quarterly Reports on Form 10-Q (as amended), Current Reports on Form 8-K, and other SEC filings, available at the SEC’s Internet site (www.sec.gov). TABLE 1 Organon & Co. Condensed Consolidated Statement of Income (Unaudited, $ in millions except shares in thousands and per share amounts) Three Months Ended September 30, Nine Months Ended September 30, 2025 2024 2025 2024 Revenues $ 1,602 $ 1,582 $ 4,709 $ 4,811 Cost of sales 745 659 2,137 1,992 Gross Profit 857 923 2,572 2,819 Selling, general and administrative 415 422 1,288 1,290 Research and development 84 111 275 339 Acquired in-process research and development and milestones — 51 6 81 Restructuring costs — — 88 23 Interest expense 128 126 383 388 Exchange losses 17 6 12 11 Other (income) expense, net (30 ) — (53 ) 9 Income before income taxes 243 207 573 678 Income tax expense (benefit) 83 (152 ) 181 (77 ) Net income $ 160 $ 359 $ 392 $ 755 Earnings per share: Basic $ 0.61 $ 1.39 $ 1.51 $ 2.94 Diluted $ 0.61 $ 1.38 $ 1.50 $ 2.92 Weighted average shares outstanding: Basic 259,975 257,498 259,266 256,830 Diluted 260,653 259,757 260,611 258,908 TABLE 2 Organon & Co. Sales by top products (Unaudited, $ in millions) Three Months Ended September 30, Nine Months Ended September 30, 2025 2024 2025 2024 ($ in millions) U.S. Int’l Total U.S. Int’l Total U.S. Int’l Total U.S. Int’l Total Women’s Health Nexplanon/Implanon NXT $ 146 $ 77 $ 223 $ 172 $ 70 $ 243 $ 486 $ 225 $ 711 $ 497 $ 207 $ 704 Follistim AQ 24 40 64 26 37 63 89 117 206 59 113 171 NuvaRing 9 17 26 7 17 23 21 54 75 33 57 90 Ganirelix Acetate Injection 3 19 22 5 20 26 10 67 77 16 65 82 Marvelon/Mercilon — 31 31 — 29 29 — 103 103 — 103 103 Jada 20 — 20 15 — 16 53 1 54 42 1 43 Other Women’s Health (1) 17 26 43 14 28 40 47 80 128 41 78 119 General Medicines Biosimilars Renflexis 51 19 70 56 16 72 141 49 190 167 43 210 Hadlima 47 16 63 29 11 40 116 44 159 71 27 98 Ontruzant 4 28 31 5 15 20 12 68 80 23 84 107 Brenzys — 23 23 — 27 27 — 59 59 — 63 63 Other Biosimilars (1) 6 3 9 — 7 7 9 13 22 — 22 22 Cardiovascular Atozet — 95 95 — 125 125 — 257 257 — 396 396 Zetia 1 91 93 2 80 81 4 248 252 5 235 240 Cozaar/Hyzaar 2 53 55 2 57 59 6 160 166 7 179 186 Vytorin 1 25 25 1 25 26 3 72 75 4 78 82 Rosuzet — 6 6 — 11 11 — 16 16 — 36 36 Other Cardiovascular (1) 1 33 33 — 27 29 1 97 98 2 97 99 Respiratory Singulair 2 51 53 2 83 85 6 187 193 7 268 275 Nasonex — 60 60 — 63 63 — 197 197 — 200 200 Dulera 24 10 34 38 10 48 89 28 118 120 31 151 Clarinex 1 25 25 1 26 27 1 92 93 2 97 100 Other Respiratory (1) 9 2 12 11 3 14 32 9 40 26 10 35 Non-Opioid Pain, Bone and Dermatology Arcoxia — 71 71 — 69 69 — 195 195 — 211 211 Fosamax — 40 40 1 37 38 2 106 107 3 109 112 Diprospan — 41 41 — 37 37 — 112 112 — 102 102 Vtama 31 3 34 — — — 80 9 89 — — — Other Non-Opioid Pain, Bone and Dermatology (1) 4 75 80 5 69 74 11 217 229 15 212 227 Other Propecia 2 31 33 2 27 28 4 86 90 5 74 79 Emgality/Rayvow — 51 51 — 29 29 — 125 125 — 69 69 Proscar — 27 27 — 23 23 1 73 73 1 72 73 Other (1) — 86 88 3 80 84 6 245 253 12 229 241 Other (2) 1 21 21 1 26 26 2 66 67 (2 ) 87 85 Revenues $ 406 $ 1,196 $ 1,602 $ 398 $ 1,184 $ 1,582 $ 1,232 $ 3,477 $ 4,709 $ 1,156 $ 3,655 $ 4,811 Totals may not foot due to rounding. Trademarks appearing above in italics are trademarks of, or are used under license by, the Organon group of companies. (1) Includes sales of products not listed separately. (2) Other includes manufacturing sales to third parties. TABLE 3 Organon & Co. Sales by geographic area (Unaudited, $ in millions) Three Months Ended September 30, Nine Months Ended September 30, 2025 2024 2025 2024 Europe and Canada $ 417 $ 436 $ 1,212 $ 1,343 United States 406 398 1,232 1,156 Asia Pacific and Japan 251 260 752 806 China 219 212 627 634 Latin America, Middle East, Russia, and Africa 286 243 810 768 Other (1) 23 33 76 104 Revenues $ 1,602 $ 1,582 $ 4,709 $ 4,811 (1) Other includes manufacturing sales to third parties. TABLE 4 Organon & Co. Reconciliation of GAAP Reported to Non-GAAP Adjusted Metrics (Unaudited, $ in millions) Three Months Ended September 30, Nine Months Ended September 30, 2025 2024 2025 2024 GAAP Gross Profit $ 857 $ 923 $ 2,572 $ 2,819 Adjusted for: Spin-related costs (1) — — — 6 Manufacturing network costs (2) 39 14 101 39 Stock-based compensation 4 4 12 13 Amortization 52 35 155 102 Acquisition-related costs (3) 12 — 31 — Other 2 — 12 — Adjusted Non-GAAP Gross Profit $ 966 $ 976 $ 2,883 $ 2,979 (1) Spin-related costs include costs from the separation of Merck & Co., Inc., Rahway, NJ, US. For additional details refer to Table 5. (2) Manufacturing network related costs include costs from exiting manufacturing and supply agreements with Merck & Co., Inc., Rahway NJ, US. For additional details refer to Table 5. (3) Acquisition-related costs relate to costs from the acquisition of Dermavant. For additional details refer to Table 5. Three Months Ended September 30, Nine Months Ended September 30, 2025 2024 2025 2024 GAAP Gross Margin 53.5 % 58.3 % 54.6 % 58.6 % Total impact of Non-GAAP adjustments 6.8 % 3.4 % 6.6 % 3.3 % Adjusted Non-GAAP Gross Margin 60.3 % 61.7 % 61.2 % 61.9 % Three Months Ended September 30, Nine Months Ended September 30, 2025 2024 2025 2024 GAAP Selling, general and administrative expenses $ 415 $ 422 $ 1,288 $ 1,290 Adjusted for: Spin-related costs (1) — (10 ) — (79 ) Stock-based compensation (16 ) (17 ) (46 ) (53 ) Restructuring related charges — — (10 ) — Other (5 ) (4 ) (34 ) (4 ) Adjusted Non-GAAP Selling, general and administrative expenses $ 394 $ 391 $ 1,198 $ 1,154 (1) Spin-related costs include costs from the separation of Merck & Co., Inc., Rahway, NJ, US. For additional details refer to Table 5. TABLE 4 Organon & Co. Reconciliation of GAAP Reported to Non-GAAP Adjusted Metrics (Continued) (Unaudited, $ in millions except per share amounts) Three Months Ended September 30, Nine Months Ended September 30, 2025 2024 2025 2024 GAAP Research and development expenses $ 84 $ 111 $ 275 $ 339 Adjusted for: Spin-related costs (1) — (2 ) — (5 ) Manufacturing network costs (2) (2 ) — (8 ) — Stock-based compensation (4 ) (4 ) (12 ) (13 ) Other (2 ) — (3 ) — Adjusted Non-GAAP Research and development expenses $ 76 $ 105 $ 252 $ 321 (1) Spin-related costs include costs from the separation of Merck & Co., Inc., Rahway, NJ, US. For additional details refer to Table 5. (2) Manufacturing network related costs include costs from exiting manufacturing and supply agreements with Merck & Co., Inc., Rahway NJ, US. For additional details refer to Table 5. Three Months Ended September 30, Nine Months Ended September 30, 2025 2024 2025 2024 GAAP Reported Net Income $ 160 $ 359 $ 392 $ 755 Adjusted for: Cost of sales adjustments 109 53 311 160 Selling, general and administrative adjustments 21 31 90 136 Research and development adjustments 8 6 23 18 Restructuring — — 88 23 Change in fair value of contingent consideration (32 ) — (9 ) — Other expense (gain), net 4 4 (37 ) 14 Tax impact on adjustments above(1) (7 ) (227 ) (69 ) (276 ) Non-GAAP Adjusted Net Income $ 263 $ 226 $ 789 $ 830 (1) For the three months ended September 30, 2025 and 2024, the GAAP income tax rates were 34.0% and (73.7)%, respectively, and the non-GAAP income tax rates were 25.3% and 24.7%, respectively. For the nine months ended September 30, 2025 and 2024, the GAAP income tax rates were 31.6% and (11.3)%, respectively, and the non-GAAP income tax rates were 24.0% and 19.3%, respectively. These adjustments represent the estimated tax impacts on the reconciling items by applying the statutory rate and applicable law of the originating territory of the non-GAAP adjustments. Three Months Ended September 30, Nine Months Ended September 30, 2025 2024 2025 2024 GAAP Diluted Earnings per Share $ 0.61 $ 1.38 $ 1.50 $ 2.92 Total impact of Non-GAAP adjustments 0.40 (0.51 ) 1.53 0.29 Non-GAAP Adjusted Diluted Earnings per Share $ 1.01 $ 0.87 $ 3.03 $ 3.21 TABLE 5 Organon & Co. Reconciliation of GAAP Net Income to Non-GAAP Adjusted EBITDA (Unaudited, $ in millions) Three Months Ended September 30, Nine Months Ended September 30, 2025 2024 2025 2024 GAAP Reported Net Income $ 160 $ 359 $ 392 $ 755 Depreciation (1) 37 32 102 93 Amortization 52 35 155 102 Interest expense 128 126 383 388 Income tax expense (benefit) 83 (152 ) 181 (77 ) EBITDA (Non-GAAP) $ 460 $ 400 $ 1,213 $ 1,261 Restructuring and related charges — — 98 23 Spin-related costs (2) — 16 — 104 Manufacturing network related (3) 46 14 118 39 Acquisition-related costs (4) 12 — 31 — Change in contingent consideration (32 ) — (9 ) — Other costs (5) 8 4 3 4 Stock-based compensation 24 25 70 79 Adjusted EBITDA (Non-GAAP) $ 518 $ 459 $ 1,524 $ 1,510 Adjusted EBITDA margin (Non-GAAP) 32.3 % 29.0 % 32.4 % 31.4 % (1) Excludes accelerated depreciation included in one-time costs. (2) Spin-related costs reflect certain costs incurred in connection with activities taken to separate Organon from Merck & Co., Inc., Rahway, NJ, US. These costs include, but are not limited to, $7 million and $47 million for the three and nine months ended September 30, 2024, respectively, for information technology infrastructure, primarily related to the implementation of a stand-alone enterprise resource planning system and redundant software licensing costs, as well as $20 million for the nine months ended September 30, 2024, associated with temporary transition service agreements with Merck & Co., Inc., Rahway, NJ, US. (3) Manufacturing network related costs, including exiting of temporary manufacturing and supply agreements with Merck & Co., Inc., Rahway, NJ, US, reflect accelerated depreciation, exit premiums, technology transfer costs, stability and qualification batch costs, and third-party contractor costs. (4) Acquisition related costs for the three and nine months ended September 30, 2025, reflect the amortization pertaining to the fair value inventory purchase accounting adjustment for the Dermavant transaction. (5) Other costs for the nine months ended September 30, 2025 include $46 million pre-tax gain related to the repurchase and cancellation of approximately $242 million of the 2031 Notes and the repayment and termination of the funding agreement with NovaQuest Co-Investment Fund VIII, L.P. and legal settlement reserves. As the costs described in (1) through (5) above are directly related to the separation of Organon and acquisition related activities and therefore arise from a one-time event outside of the ordinary course of the company’s operations, the adjustment of these items provides meaningful, supplemental, information that the company believes will enhance an investor's understanding of the company's ongoing operating performance.

编辑：丹青 胆汁淤积性肝损伤（cholestatic liver injury，CLI）是由于遗传缺陷、机械畸变、毒素或免疫系统失调等因素使胆汁代谢障碍，有毒胆汁淤积于肝脏、胆管和胆囊对肝胆系统造成损伤的病理状态[1]。根据胆汁淤积部位分为肝外与肝内胆汁淤积症。肝外胆汁淤积症对应于肝外胆道梗阻，以结石、肿瘤、胆道闭锁和原发性硬化性胆管炎为诱因；肝内胆汁淤积症则以药物、遗传转运蛋白缺陷、感染和原发期胆汁性肝硬化为诱因[2]。胆汁淤积的典型症状为黄疸、尿色深、粪便色浅、皮肤瘙痒，长期淤积还将导致皮肤色泽暗沉和皮下黄色脂肪沉积。研究表明，胆汁酸稳态失衡[3]、炎症反应[4]、氧化应激[5]是CLI发展的关键。 目前，熊去氧胆酸（ursodeoxycholic acid，UDCA）与奥贝胆酸分别作为CLI的主流治疗药物。然而，UDCA存在瘙痒、疲劳等不良反应，不能提高患者生存率，部分患者对其治疗应答不充分或无应答[6]等问题。奥贝胆酸则存在对肝细胞凋亡无效，剂量相关性瘙痒[7]等问题。相比于化学类药物，天然活性药物来源多样，易于提制且成本低廉；在治疗方面集聚多靶点、高疗效、不良反应少等优势[8]。因此，深入了解CLI发展机制，寻找天然活性药物及潜在治疗靶点至关重要。 黄酮类化合物是广泛存在于黄芩、银杏叶、葛根等中药的一种多酚类次生代谢产物[9]，其数量庞大、结构多样，根据结构可分为黄酮、黄酮醇、黄烷酮、黄烷醇等12个亚型[10]。该类化合物具有良好的抗炎、抗氧化、保肝等生物活性[11]，在胆汁淤积[12-13]、肝纤维化[14]、非酒精性脂肪肝[15]、肝癌[16]等肝病模型中均表现出良好疗效，可通过恢复胆汁酸稳态、抑制炎症反应和氧化应激等机制改善CLI。因此，本文就黄酮类化合物对CLI的治疗作用和相关机制进行综述，为黄酮类化合物治疗CLI的临床应用和新药开发提供依据。 1  CLI的病理机制 1.1  胆汁酸稳态失衡 胆汁酸是胆汁的主要成分，与细胞增殖、凋亡、自噬[17]、炎症反应[18]、肠道菌群[19]等相关。生理条件下，人肝细胞利用胆固醇分别由经典途径与替代途径生成以鹅去氧胆酸（chenodeoxycholic acid，CDCA）与胆酸为主的初级胆汁酸。随后经胆汁酸辅酶A合成酶（bile acid coenzyme A synthetase，BACS）和胆汁酸辅酶A：氨基酸N-乙酰基转移酶（bile acid-coenzyme A: amino acid N-acyltransferase，BAAT）作用与甘氨酸或牛磺酸结合为甘氨鹅脱氧胆酸（glycochenodeoxycholic acid，GCDCA）、甘氨胆酸（glycocholic acid，GCA）、牛磺鹅脱氧胆酸（taurochenodeoxycholic acid，TCDCA）、牛磺胆酸（taurocholic acid，TCA）结合型胆汁酸，并被胆盐输出泵（bile salt export pump，BSEP）分泌；也可经过磺基转移酶（sulfotransferases，SULTs）磺化或UDP-葡萄糖醛酸转移酶（UDP-glucuronosyl-transferases，UGTs）葡糖醛酸化后被多药耐药相关蛋白2（multidrug resistance-associated protein 2，MRP2）分泌。这些被分泌的胆汁酸部分存储于胆囊，另一部分随十二指肠进入肠道。进入肠道的结合型胆汁酸在肠道菌群的作用下被转化为以去氧胆酸和石胆酸为主的次级胆汁酸。对于非结合型胆汁酸，大部分去氧胆酸、CDCA、胆酸和少量石胆酸于回肠末端被肠细胞的顶端钠依赖性胆汁酸转运蛋白（apical sodium-dependent bile acid transporter，ASBT）重吸收，并通过有机溶质转运蛋白（organic solute transporter，OST）α/β、MRP2/3进入门静脉，最后经牛磺胆酸钠共转运蛋白（sodium taurocholate cotransporting polypeptide，NTCP）和有机阴离子转运多肽1（organic anion-transporting polypeptide 1，OATP1）重新进入肝细胞[20-21]。另外，肝细胞的OSTα/β和MRP3/4还为胆汁酸排泄进入体循环提供了途径[22-23]。然而，转运蛋白受病理因素影响促使胆汁酸循环障碍是引发胆汁淤积较为关键的原因，并且胆汁淤积又必然伴随胆汁酸浓度和成分的变化[3]。因此，从胆汁酸循环和胆汁酸浓度与成分的变化入手，是深入了解胆汁酸稳态失衡的关键。 NTCP、OATP、MRP等与胆汁酸循环密切相关[24-25]。研究者认为，大多数药物对这些运输系统所造成的影响都有可能成为造成胆汁淤积的潜在因素[26]，如利福平可抑制NTCP、MRP2、OATP1A1和OATP1A4等功能[27]；他莫昔芬可抑制MRP2、MRP3、MRP4等功能[28]。转运体功能的异常干扰胆汁酸循环，高浓度胆汁酸积于肝内，可能产生细胞毒性[29]。 胆汁酸在组织中浓度与其内在活性的关系已被证明[30]。胆汁酸浓度介于15～25 μmol/L可作为信号分子，浓度达50～200 μmol/L将引起细胞凋亡，接近200 μmol/L时激活促炎基因，浓度升高至200～2 000 μmol/L将诱导细胞坏死，高于2 000 μmol/L既作为洗涤剂也可诱导细胞坏死，见图1。正常条件下，胆汁中的胆汁酸存在于混合胶束，其固有细胞毒性被其中的磷脂和胆固醇中和[31]。而在病理生理状态下，炎症反应使胆-血屏障受损，对胆汁酸抵抗力弱的导管周围基质和基底外侧质膜域暴露于高浓度的有毒胆汁酸中，加重炎症与损伤[32]。也有研究者认为，胆管与胆小管的渗漏更有可能是胆汁淤积性肝病的原因和持续的主要因素[30]。 1.2  炎症反应 炎症反应是梗阻性、雌激素或药物性胆汁淤积症患者的常见并发症，与胆汁酸表达水平密切相关，是CLI的中心事件之一[4]。在病理条件下，毒性胆汁酸对肝脏的损伤并非直接源于其本身具有的细胞溶解特性，而是其通过诱导胆汁淤积型肝细胞释放细胞因子或介导免疫细胞对肝的浸润等机制间接实现的[33]。在肝细胞水平，胆汁酸能激活肝细胞中各信号通路进而上调促炎基因[4,34]。这些通路中有丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）、早期生长反应因子1（early growth response 1，EGR1）、脂多糖、核因子-κB（nuclear factor-κB，NF-κB）及孕烷X受体（pregnane X receptor，PXR）等的参与。Allen等[34]发现小鼠肝细胞暴露于胆汁酸会增加白细胞介素（interleukin，IL）、趋化因子[如角质形成细胞衍生趋化因子（keratinocyte-derived chemokine，KC）、巨噬细胞炎症蛋白-2（macrophage inflammatory protein-2，MIP-2）]、黏附分子[如细胞间黏附分子-1（intercellular adhesion molecule-1，ICAM-1）、血管细胞黏附分子-1（vascular cell adhesion molecule-1，VCAM-1）]、花生四烯酸代谢酶[如环氧合酶-2（cyclooxygenase-2，COX-2）]等介质的水平。这些介质受到信号通路与促炎介质的调控，其中ICAM-1、MIP-2、KC的上调已被证明能促进CLI[35-36]。GCDCA是人体的主要胆汁酸，Cai等[37]将人肝细胞暴露于GCDCA中，检测到细胞中C-C基序趋化因子配体2（C-C motif chemokine ligand 2，CCL2）、CCL15、CCL20、C-X-C基序趋化因子配体1（C-X-C motif ligand 1，CXCL1）、IL-8的表达显著提升并伴有线粒体损伤的现象。线粒体损伤可能释放损伤相关分子模式（damage associated molecular patterns，DAMPs）并通过Toll样受体（toll-like receptors，TLR）促进炎症因子表达[38]。 中性粒细胞（neutrophil，NE）在肝坏死部位的浸润是CLI的显著特征。相比其他炎症细胞，其介导的炎症反应被认为与CLI最为相关[39]。病理生理条件下，补体成分5a（complement component 5a，C5a）、脂多糖、细胞因子等与NE的活化相关；受损细胞释放的DAMPs、细胞间黏附分子-1（intercellular cell adhesion molecule-1，ICAM-1）、细胞骨架连接蛋白（ezrin-radixin-moesin，ERM）和钠氢交换调控因子1（Na+/H+exchanger regulatory factor-1，NHERF-1）则与NE的募集相关[40]。这些因素均有助中性粒细胞靶向杀死应激和受伤的肝细胞。值得注意的是，NE还产生丝氨酸蛋白酶，这种物质不仅有细胞毒性还能参与炎症细胞因子的活化，加重肝损伤[41]，见图2。 1.3 氧化应激 氧化应激由活性氧与抗氧化系统失衡所致，是CLI的常见特征。线粒体富含于肝细胞，作为胆汁酸影响的主要靶点，是活性氧的主要来源。高水平毒性胆汁酸可通过降低线粒体状态III呼吸速率和膜电位、下调抗凋亡蛋白B淋巴细胞瘤-2（B-cell lymphoma-2，Bcl-2）的表达并上调促凋亡蛋白Bcl-2相关X蛋白（Bcl-2 associated X protein，Bax）的表达、增加线粒体过氧化氢和脂质过氧化产物的积累，进而严重影响线粒体功能[42-43]。因此，毒性胆汁酸可在线粒体水平上诱导活性氧的释放，造成DNA损伤、蛋白质氧化、细胞膜损伤等。内质网应激（endoplasmic reticulum stress，ERS）也由毒性胆汁酸引起，钙离子由内质网向胞质释放，使胞质形成高浓度的钙离子环境是线粒体释放活性氧的诱因之一[44]。被释放的活性氧可以反向刺激线粒体渗透性转换孔（mitochondrial permeability transition pore，MPTP），胞质中大量高分子的渗入最终引起线粒体膜损伤[45]。此外，炎症反应中受刺激的中性粒细胞亦可通过激活NADPH氧化酶2（NADPH oxidase 2，NOX2）催化产生活性氧与次氯酸参与氧化应激[46]，见图3。 2  治疗CLI的黄酮类化合物 黄酮类化合物是一类以二苯丙烷（C6-C3-C6）骨架为核心结构的多酚类物质，生物活性广泛，在胆汁淤积、肝纤维化、非酒精性脂肪肝、肝癌等疾病中均有疗效。本文根据分子结构特征总结了近年来各类黄酮类化合物治疗CLI的作用机制。 2.1  黄酮类 2.1.1  黄芩苷 黄芩苷主要存在黄芩干燥根中，其对CLI的治疗机制报道较多。Yang等[47]用17α-乙炔基雌二醇（17α-ethinylestradiol，EE）诱导的胆汁淤积症大鼠，证明黄芩苷主要通过激活沉默调节蛋白1（sirtuin 1，Sirt1）/肝细胞核因子-1α（hepatocyte nuclear factor-1α，HNF-1α）/法尼醇X受体（farnesoid X receptor，FXR）信号通路来实现保肝作用。在胆汁酸稳态中，黄芩苷恢复FXR与胆汁酸代谢酶[细胞色素P450 3A2（cytochrome P450 3A2，CYP3A2）、BACS、BAAT和磺基转移酶家族2A成员1（sulfotransferase family 2A member 1，SULT2A1）] 的表达，减少胆汁酸合成并促进其代谢；下调NTCP，抑制了胆汁酸摄取；增加BSEP、MRP2～4的mRNA表达，促进胆汁酸外排。在炎症反应中，黄芩苷可能通过抑制NF-κB信号转导，从而逆转EE诱导的肿瘤坏死因子-α（tumor necrosis factor-α，TNF-α）、IL-1β、IL-6高表达。Shen等[48]运用胆管结扎（bile duct ligation，BDL）小鼠，证明黄芩苷可从氧化应激、硝化应激、炎症、细胞死亡及调节星状细胞活化来起到保肝作用。在氧化应激与硝化应激中，黄芩苷可降低NOX2和诱导型一氧化氮合酶（inducible nitric oxide synthase，iNOS）的表达，及肝脏中4-羟基壬烯醛（4-hydroxynonenal，HNE）蛋白加合物与蛋白质硝化水平，改善氧化应激与硝化应激；增强核因子E2相关因子2（nuclear factor E2-related factor 2，Nrf2）核易位，使抗氧化防御增强；还可提高线粒体中复合体I/II/IV的活性，改善线粒体功能。在炎症反应中，使促炎因子TNF-α、IL-1β、MIP-1α、和MIP-2水平降低。在细胞凋亡中，减少DNA断裂，降低DNA修复酶（poly ADP-ribose polymerase，PARP）与含半胱氨酸天冬氨酸蛋白酶-3（cystein-asparate protease-3，Caspase-3）活性。此外，黄芩苷可下调胶原蛋白I、纤维连接蛋白、α-平滑肌动蛋白（α-smooth muscle actin，α-SMA）和CTGF的mRNA，调节星状细胞活化从而减轻肝纤维化。王晓霞等[49]发现黄芩苷和姜黄素联用可降低肝内CYP7A1、CYP8B1表达；增加BSEP、MRP2并降低MRP4表达；逆转胆汁淤积中CYP3A4、SULT2A1的低表达水平，显著改善乙醇诱导的CLI。 2.1.2 牡荆素 牡荆素是主要存在山楂干燥叶中，对神经、肾脏、肝脏等均有保护作用[50-51]。然而，牡荆素对CLI的针对性报道较为少见，且作用机制有待阐明。Zhang等[52]表明牡荆素通过上调Sirt6表达，降低GCDCA诱导的永生化人肝上皮THLE-3细胞中活性氧、丙二醛水平，并提高超氧化物歧化酶（superoxide dismutase，SOD）、谷胱甘肽水平；抑制Janus激酶2（Janus kinase 2，JAK2）/信号转导和转录激活因子3（signal transducer and activator of transcription 3，STAT3）通路；升高基质金属蛋白酶（matrix metalloproteinase，MMP）水平，通过多机制减轻GCDCA诱导的氧化应激和细胞凋亡。 2.1.3 芹菜素 芹菜素主要以糖苷形式存在于洋甘菊和欧芹等植物中，具有抗氧化、抗肿瘤的作用[53]。Zheng等[54]发现芹菜素可从多机制改善3,5-二乙氧基羰基-1,4-二氢可力丁（3,5-diethoxycarbonyl-1,4-dihydrocollidine，DDC）诱导的小鼠CLI。其机制包括逆转由DDC诱导的小鼠肝脏中FXR/小异二聚体配体（small heterodimer partner，SHP）、CYP7A1、CYP8B1、BSEP、ATP结合盒转运蛋白B4（ATP-binding cassette transporter B4，ABCB4）、ABCG5的低表达从而改善胆汁酸稳态；降低模型组小鼠肝脏中γ-谷氨酰转肽酶（γ-glutamyl transpeptidase，γ-GT）及血清中天冬氨酸氨基转移酶（aspartate aminotransferase，AST）、丙氨酸氨基转移酶（alanine aminotransferase，ALT）、碱性磷酸酶（alkaline phosphatase，ALP）活性减少肝损伤。其次，芹菜素也能抑制肝脏中TLR4/NF-κB/TNF-α炎症途径，减少炎症反应。另外，转化生长因子-β（transforming growth factor-β，TGF-β）、α-SMA和I型胶原α1链（collagen type I α1 chain，COL1A1）的表达亦可被芹菜素抑制，这抑制了肝细胞纤维化。 2.1.4 地奥司明 地奥司明是一种柑橘衍生的生物类黄酮，有效且安全[55]。Ali等[56]探讨地奥司明与西地那非单药或联合后处理对BDL大鼠的保护作用，并发现两种干预方式均可升高白蛋白水平，降低ALT、AST、ALP、γ-GT、胆红素水平，改善所有肝功能生物标志物；其次，2种干预方式均可提高细胞珠蛋白水平，并下调羟脯氨酸与TGF-β水平；抑制P38-MAPK/NF-κB-p65/iNOS信号通路；升高肝组织中谷胱甘肽、SOD并降低丙二醛水平。以上分别通过抗纤维化、抗炎症反应、抗氧化应激，进而改善CLI。另外，地奥司明与西地那非也能上调Kelch样ECH关联蛋白-1/Nrf2，通过提升内源性抗氧化补充能力，实现抗氧化水平的提高。 2.1.5木犀草素 木犀草素存在于芹菜、菊花、胡萝卜、洋葱叶、西兰花等植物中[57]，主要用于治疗急性肝损伤、药源性肝损伤、酒精性肝病等疾病[58]。Lee等[59]用木犀草素抑制D-氨基半乳糖＋脂多糖诱导的肝损伤小鼠ALT、TNF-α和Caspase-3/8的表达。同时，木犀草素可减少胞浆细胞色素C和c-Jun氨基末端激酶（c-Jun N-terminal kinase，JNK）磷酸化并抑制肿瘤坏死因子受体相关死亡结构域蛋白的表达，从抗炎和抗凋亡机制减少肝损伤。Yang等[60]将木犀草素与二甲双胍联用，抑制了CCl4诱导肝损伤大鼠中IL-6、IL-1β、TNF-α水平的异常升高；其次激活Nrf2/血红素加氧酶-1（heme oxygenase-1，HO-1）通路增加抗氧化防御；在抗凋亡机制中，激活Bcl-2并降低caspase-3与Bax表达，进而通过多机制发挥疗效。Wu等[61]还将木犀草素和白藜芦醇联用，发现其对α-萘异硫氰酸盐（α-naphthyl isothiocyanate，ANIT）诱导胆汁淤积症大鼠的治疗作用与调节胆汁酸稳态和抗氧化应激密切相关。 2.2 黄酮醇类 2.2.1  槲皮素 槲皮素是广泛存在于茶和洋葱中的植物色素，在非酒精性脂肪肝、肝肺综合征、急性肝衰竭等疾病中的保护机制均有报道[62-63]。Lin等[64]发现槲皮素可能通过抑制TGF-β1/Smad2/3信号通路、干扰TLR4信号通路、下调NF-κB活性，最终改善BDL诱导的大鼠胆汁淤积性损伤。Kabirifar等[65]证明槲皮素恢复BDL大鼠胆汁淤积中Ras相关C3肉毒毒素底物1（Ras-related C3 botulinum toxin substrate 1，Rac1）、鸟苷三磷酸（guanosine triphosphate，GTP）、Rac1-GTP、NOX1的mRNA异常表达。此外，槲皮素还上调谷胱甘肽过氧化物酶的活性，减弱BDL大鼠肝脏中的氧化应激[66]。Wu等[67]则用BDL和CCl4诱导的肝硬化小鼠模型，证明槲皮素对TGF-β1/Smads信号通路的抑制和磷酸肌醇3-激酶（phosphoinositide 3-kinase，PI3K）/蛋白激酶B（protein kinase B，Akt）信号通路的激活是其抗纤维化的重要靶点。除用槲皮素单独做后处理外，当其与西地那非或己酮可可碱联用，可通过调节Nrf2/抗氧化反应元件、NOD样受体家族含pyrin结构域蛋白3（NOD-like receptor family pyrin domain containing 3，NLRP3）/IL-1β、TLR4/NF-κB信号通路减少ANIT诱导CLI大鼠肝细胞炎症与细胞焦亡[68]。 2.2.2 芦丁 芦丁是广泛存在于槐、芸香、红旱莲等植物中的黄酮醇类化合物[69]，常用于治疗心脑血管疾病，也具有降血糖和调血脂[70]、保护肝脏等作用。Pan等[71]首次报道芦丁对CLI有保护作用，这可能与其下调NF-κB与TGF-β/Smad信号通路，干扰细胞外信号调节激酶活化，增强Nrf2、HO-1和腺苷酸活化蛋白激酶活性有关。Ahmed等[72]研究发现，单用芦丁或与槲皮素联用，在阿霉素诱导的肝损伤大鼠中表现抗炎、抗氧化、保护肝细胞的作用；同时这2种干预方案均可降低血清中ALT、AST、ALP、总胆红素水平，升高白蛋白水平，使肝胆系统得以改善。此外，还能降低肝脏中脂质过氧化物浓度及p53和TNF-α表达；提高谷胱甘肽浓度及谷胱甘肽过氧化物酶（glutathione peroxidase，GSH-Px）、谷胱甘肽S-转移酶（glutathione S-transferase，GST）、SOD活性和Nrf2表达，缓解氧化应激状态和炎症反应并增强抗氧化防御系统。 2.2.3  异鼠李素 异鼠李素是沙棘果实和银杏叶中最重要的活性成分之一，具有抗肿瘤、保护心血管、保护肝脏等活性[73]。Liu等[74]报道异鼠李素通过下调TGF-β1/Smad3与TGF-β1/p38 MAPK信号通路，改善CCl4和BDL诱导的小鼠肝纤维化。作为异鼠李素的衍生物的异鼠李素-3-O-芦丁苷也可能改善溴氰菊酯诱导的大鼠肝损伤[75]，在生化指标上，其改善溴氰菊酯大鼠的AST、ALT、乳酸脱氢酶（lactate dehydrogenase，LDH）、ALP、SOD、过氧化氢酶（catalase，CAT）、GSH-Px、谷胱甘肽等水平；在抗炎机制上，抑制NF-κB基因，减少TNF-α、IL-1β、IL-6等促炎因子；在抗凋亡机制上，减弱Caspase-3、p53的mRNA激活。另外，还能降低肝组织中α-SMA、I型胶原蛋白和TGF-β1的mRNA高表达，进而抗纤维化。 2.2.4 水飞蓟素 水飞蓟素是水飞蓟提取物的主要成分，由8种黄酮类化合物组成。其中，水飞蓟宾的生物活性最强[76]。水飞蓟素活性广泛，保肝作用尤为显著，常用于慢性肝病、肝硬化、肝细胞癌等疾病[77]。Crocenzi等[78]发现水飞蓟素通过减少ALP，增加HCO3−输出与胆汁排泄量改善EE诱导的大鼠胆汁淤积；同时还报道水飞蓟素能够提高牛磺石胆酸诱导胆汁淤积症大鼠的胆汁流量、总胆盐输出量及胆汁中谷胱甘肽与HCO3−的分泌量，使胆汁淤积得以缓解[79]。Sohail等[80]探究水飞蓟素改善ANIT小鼠胆汁淤积症状，其机制与上调FXR、BSEP、NTCP表达，降低CYP7A1表达有关，这主要通过对胆酸稳态相关基因的调控从而减轻肝损伤。此外，水飞蓟素包被的金纳米颗粒对胆汁淤积症的疗效优于水飞蓟素单药治疗[81]，水飞蓟素包被金纳米颗粒能改善BDL大鼠AST、ALT、丙二醛等水平；降低p-NF-κB、TGF-β1表达；抑制TGF-β释放，下调α-SMA水平，从生化指标、炎症反应、氧化应激和纤维化水平等方面表明水飞蓟素能减轻CLI，恢复肝功能。 2.2.5  黄蜀葵花总黄酮 黄蜀葵花总黄酮（the total flavonoids extracted from Abelmoschi Corolla，TFA）是从黄蜀葵花提取而来，主含槲皮素、杨梅素、金丝桃苷等7种黄酮醇类化合物[82]，传统用黄蜀葵花汤剂治疗各类肝炎。Ai等[83]用CCl4诱导肝损伤模型，在体外实验中，TFA显著降低模型组培养液中ALT、AST、ALP浓度，且细胞存活率与TFA浓度呈相关性增加。在动物实验中，TFA改善模型组中ALT、AST、ALP、γ-GT、谷胱甘肽各生化指标；提高SOD、GSH-Px、CAT、GST等抗氧化酶活性，并抑制TNF-α、IL-1β、一氧化氮等炎症介质。因而，TFA通过抗炎和抗氧化应激保护肝细胞损伤。Yan等[84]发现TFA干预ANIT诱导的CLI大鼠后，症状同样得到改善；除改善生化指标、抗氧化酶活性、抑制炎症介质外，TFA还提高BSEP、MRP2、NTCP表达，促进胆汁酸流动。 2.3  二氢黄酮类 2.3.1 橙皮苷 橙皮苷主要存在于柑橘类植物中，是治疗心血管疾病、癌症、肝病的潜在药物[85]。在早期报道中，橙皮苷单药治疗可有效降低CCl4诱导的肝损伤大鼠中脂质过氧化、NF-κB、TGF-β、CTGF、IL-1β水平，增加IL-10的水平[86]，从抗炎抗氧化机制解释了橙皮苷的保肝作用。随后，Zhang等[87]验证橙皮苷通过改善胆汁酸循环，缓解肝损伤。研究者采用ANIT小鼠模型与FXR抑制的人肝癌HepaRG细胞，发现橙皮苷可逆转ANIT诱导的血清中ALT、AST、总胆汁酸、总胆红素、ALP、γ-GT水平升高；上调FXR、SHP、OATP1A1、BSEP和MRP2，并降低CYP7A1、CYP27A1、NTCP、ASBT表达，通过减少胆汁酸合成与摄取，增加排泄，最终减少胆汁淤积。 2.3.2 甘草素与甘草苷 甘草素为甘草苷的苷元，二者是甘草中主要活性成分，具有抗炎、抗氧化、抗肿瘤、保肝等活性[88-89]。Lee等[90]认为甘草素通过促进Yes相关蛋白（Yes-associated protein，YAP）磷酸化，进而抑制肝星状细胞（hepatic stellate cells，HSC）活化和TGF-β1/Smad信号通路，从而改善CCl4诱导的小鼠肝纤维化。Yan等[91]表明甘草苷降低ANIT诱导的丙二醛、TNF-α、IL-1β升高；其次，减弱ANIT对小鼠肝组织中Sirt1和FXR表达的抑制，并增加Nrf2核表达；此外，还增加胆汁酸转运蛋白BSEP、NTCP、MRP3和MRP4的mRNA表达。表明甘草苷通过调节Sirt1/FXR/Nrf2通路与胆汁酸转运蛋白，进而减轻CLI。 2.4 异黄酮类 2.4.1 鸢尾黄素 鸢尾黄素主要存在于射干、鸢尾花等药材中，在非酒精性脂肪性肝病、肝衰竭、肝癌的动物模型中均表现出保肝作用[92-93]。Xiang等[94]表明鸢尾黄素能改善ANIT、DDC诱导的CLI。鸢尾黄素作为过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor γ，PPARγ）的部分激动剂[95]，通过激活PPARγ，进而可能抑制NF-κB通路，通过调节PPARγ/NF-κB通路，干扰巨噬细胞活化；其次，能够抑制KC活化，减少IL-1β、TNF-α等促炎因子释放，同时阻断NF-κB-p65磷酸化，减少肝细胞凋亡；另外，鸢尾黄素还上调BSEP，减轻肝内胆汁淤积。 2.4.2  刺芒柄花素 刺芒柄花素（formononetin，FORM）是植物雌激素中的一种异黄酮，主要存在大豆和红三叶草中，常用于自身免疫性肝炎、肝损伤、肝中毒等疾病[96-97]。Yang等[98]报道FORM对ANIT诱导的胆汁淤积症小鼠的肝保护作用，FORM通过激活Sirt1/FXR信号通路，上调BSEP和MRP2的表达；逆转ANIT诱导的NTCP抑制作用；刺激PPARα使JNK通路失活。由此，FORM既改善胆汁酸稳态又抑制炎症。 2.4.3  染料木素 染料木素又称金雀异黄酮，主要存在大豆中。Salas等[99]用染料木素处理BDL大鼠，发现肝脏中胶原蛋白含量、总胆红素、ALP、ALT、γ-GT等各血清标志物显著降低。尽管染料木素能够恢复肝损伤大鼠的谷胱甘肽水平、降低肝脏脂肪堆积[100]，但仍缺乏染料木素改善CLI分子机制的直接证据。 2.5 黄烷醇类 表没食子儿茶素没食子酸酯[(−)-epigallocatechin gallate，EGCG] 是由表没食子儿茶素和没食子酸形成的黄烷-3-醇类化合物。EGCG具有抗炎、抗氧化、抗纤维化作用，在肝性脑病、非酒精性脂肪性肝病、肝癌等动物模型中均具肝保护作用[101-102]。Zhong等[103]、Kobayashi等[104]报道山茶中多酚类化合物与绿茶儿茶素混合物减少BDL大鼠的肝损伤，并暗示EGCG作为其中主要成分可能起主要保护作用。Hirsova等[105]指出EGCG通过降低MRP2表达，从而减少EE诱导的胆汁淤积症大鼠中MRP2依赖性胆汁流量，有助缓解胆汁淤积。值得注意的是，EGCG也能上调胆汁酸合成限速酶CYP7A1，因而长期或高剂量使用EGCG存在诱导胆汁淤积的可能。Yu等[106]阐述EGCG在BDL大鼠与TGF-β1刺激的人肝星状LX-2细胞中抗纤维化的分子机制，EGCG能显著降低BDL大鼠纤维化相关基因TNF-α、IL-1β、TGF-β1、MMP9、α-SMA和COL1A1的表达；在LX-2细胞中，EGCG可呈剂量相关性抑制COL1A1、MMP2、MMP9、TGF-β1、基质金属蛋白酶组织抑制因子1、α-SMA的表达；此外，Smad2/3和Akt的磷酸化被EGCG抑制，表明PI3K/Akt/Smad通路介导了EGCG的抗纤维作用。 3  结语与展望 CLI是胆汁分泌排泄受损使肝内胆汁酸过度积累，从而导致胆管和肝细胞均受损的病理状态，其中胆汁酸稳态失衡、炎症反应、氧化应激作为CLI发展的关键，是控制和治疗疾病的突破点。黄酮类化合物在治疗CLI存在多种潜在作用机制，包括改善胆汁酸稳态失衡、抗氧化应激、抗炎症反应、抗细胞凋亡、抗纤维化等。几乎所有黄酮类化合物均能通过抗炎和抗氧化机制发挥保肝作用，部分化合物如黄芩苷、芹菜素、水飞蓟素、TFA、橙皮苷、甘草素、甘草苷、FORM、染料木素、EGCG能调节胆汁酸稳态相关基因及胆汁酸转运蛋白来改善胆汁酸流量，从而通过恢复胆汁酸稳态机制发挥作用。此外，黄芩苷、芹菜素、地奥司明、槲皮素、异鼠李素、水飞蓟素、甘草素、EGCG还能通过抗纤维化保护肝脏。黄酮类化合物的保肝作用机制主要涉及JAK2/STAT3、p38 MAPK/NF-κB-p65/iNOS、TGF-β1/Smad2/3、TLR4、Sirt1/FXR/Nrf2、PI3K/Akt/ Smad和Nrf2/HO-1等信号通路。研究报道，在黄酮类化合物治疗CLI的机制研究中，常以黄酮类和黄酮醇类化合物干预给药，其分子机制相对明确。在对CLI联合干预治疗机制的研究中，黄芩苷、地奥司明、槲皮素、芦丁、木犀草素均有报道。值得注意的是，近期研究热点正向新黄酮类化合物亚型拓展，目前柚皮素[107]和反式查耳酮[108]具抗肝纤维化作用已被报道，这为研究黄酮类化合物治疗CLI的作用机制提供了新视角。 目前，主要集中在黄酮类化合物与肝病的研究，而与CLI的研究相对较少。由于黄酮类化合物的种类和数量丰富，其构效关系尚不明确。同时，CLI发病机制复杂且药物作用靶点多样，以往对CLI发病机制的阐述聚焦炎症反应或氧化应激，鲜有报道从胆汁酸稳态角度系统阐述胆汁酸的流动、代谢过程及其浓度和成分变化与CLI的关联性，若将胆汁酸稳态、炎症反应、氧化应激结合并进一步探讨三者关联有望成为阐述CLI复杂机制的新视角。对于黄酮类化合物治疗靶点的研究思路大致可归为2类：一类由胆汁酸稳态角度，以胆汁酸转运蛋白或输出泵为主体，侧重观察胆汁酸流动指标的变化及相关酶活性或基因表达情况，而在机制阐述中仅少数涉及信号通路；另一类则从炎症反应与氧化应激角度，以生物分子为主体，侧重生化指标的变化及生物分子间信号关联，在已知的黄酮类化合物改善CLI所涉及的信号通路中，几乎都在下游交汇于NF-κB信号，其与之上游信号（如TGF-β、NLRP3和TLR4等）的关系正日益明晰，而Hippo、PPARγ、Nrf2等信号在病理过程中的变化虽已有报道，但在CLI中与其他信号的关联尚且不明确，有待进一步探索。因而黄酮类化合物对CLI的具体靶点与作用机制还需深入探究。其次，临床研究有待加强，实验模型多数采用BDL法或化学试剂诱导的胆汁淤积大小鼠模型，少数使用LX-2、HepaRG和THLE-3细胞。BDL法多指对胆总管完全结扎，模型构建耗时短，模拟临床上胆石性肝病和胆道闭锁，通常在术后早期即可观察到肝损伤和梗阻情况指标的明显变化，多用于急性胆汁淤积的研究，然而存在术后死亡率高和存活期短的问题[109]；化学诱导法虽操作简单且成功率高，可模拟药源性胆汁淤积症，肝损伤指标在建模期间逐渐上升，常用于慢性胆汁淤积的研究，但模型构建周期长[110]。近年来，部分胆管结扎术被报道可能成为肝损伤相关机制的新构建模型方式，该法在短时间内完成建模的同时显著降低术后死亡率并增加存活期限，这将延长对术后实验动物各生化指标的监测周期，提高过程性评估与结论的准确性[111]。此外，为降低部分黄酮类化合物潜在的副作用，保证疗效的同时还需要进一步调整和明确给药剂量，及研究药物联用的疗效问题。鉴于黄酮类化合物有良好的抗胆汁淤积药理活性，对近年来天然黄酮类化合物改善CLI的基础研究进行总结和梳理具有重要意义。因此，本文就药用植物中黄酮类成分对CLI的相关机制进行归纳，综述目前防治CLI黄酮类药物的研究进展，体现天然黄酮类化合物在治疗胆汁淤积型肝病中具有广泛的应用前景，为其进一步其临床应用和新药研发提供参考。 利益冲突  所有作者均声明不存在利益冲突 参考文献（略） 来  源：刘明睿，董佳豪，袁  铖，吴  昊，钱冰露，高子涵，刘应蛟．黄酮类化合物在胆汁淤积性肝损伤治疗中的作用及机制研究进展  [J]. 中草药, 2025, 56(16): 5981-5993 END 文章内容仅供思路参考，不代表本刊观点，非中医药专业人员请勿试药 文章来源:中草药杂志社 ，本草全球转载仅为传播行业信息，不做商业用途。若转载不当，请联系：28331285@163.com删除，感谢原作者的辛劳付出。文中插入广告与本公众号无关。 本草全球服务内容  包括但不限于:  中药新药、经典名方、配方颗粒、中药CMC、美国FDA IND、中药保护品种临床试验申报、中药上市再评价、药物经济学评价、新药研发及中药类注册备案全过程咨询与委托服务;可为有关单位疑难问题提供解决方案与技术支持、开展内训等服务。凡提交至本草全球的疑难问题,均可协助解决。  联系人:田先生 13801667235