Ranolazine

Camzyos has the potential to be the first pharmacological therapy for the treatment of oHCM in adolescents, addressing a high unmet need for this population Application based on positive results of Phase 3 SCOUT-HCM trial, which met its primary endpoint with safety pro to established pro adults PRINCETON, N.J.--(BUSINESS WIRE)-- $BMY #CAMZYOS -- Bristol Myers Squibb (NYSE: BMY) today announced the U.S. Food and Drug Administration (FDA) accepted a supplemental New Drug Application (sNDA) for Camzyos (mavacamten) as a potential treatment for adolescents (ages 12 years to 5% of patients and more commonly in the CAMZYOS group than in the placebo group were dizziness (27% vs 18%) and syncope (6% vs 2%). There were no new adverse reactions identified in VALOR-HCM. Effects on Systolic Function In the EXPLORER-HCM trial, mean (SD) resting LVEF was 74% (6) at baseline in both treatment groups. Mean (SD) absolute change from baseline in LVEF was -4% (8) in the CAMZYOS group and 0% (7) in the placebo group over the 30-week treatment period. At Week 38, following an 8-week interruption of trial drug, mean LVEF was similar to baseline for both treatment groups. In the EXPLORER-HCM trial, 7 (6%) patients in the CAMZYOS group and 2 (2%) patients in the placebo group experienced reversible reductions in LVEF <50% (median 48%: range 35-49%) while on treatment. In all 7 patients treated with CAMZYOS, LVEF recovered following interruption of CAMZYOS. DRUG INTERACTIONS Potential for Other Drugs to Affect Plasma Concentrations of CAMZYOS CAMZYOS is primarily metabolized by CYP2C19 and to a lesser extent by CYP3A4 and CYP2C9. Inducers and inhibitors of CYP2C19 and moderate to strong inhibitors or inducers of CYP3A4 may affect the exposures of CAMZYOS. Impact of Other Drugs on CAMZYOS: Strong CYP2C19 Inhibitors : Concomitant use increases CAMZYOS exposure, which may increase the risk of heart failure due to systolic dysfunction. Concomitant use is contraindicated. Moderate to Strong CYP2C19 Inducers or Moderate to Strong CYP3A4 Inducers : Concomitant use decreases CAMZYOS exposure, which may reduce CAMZYOS’ efficacy. The risk of heart failure due to systolic dysfunction may increase with discontinuation of these inducers as the levels of induced enzyme normalizes. Concomitant use is contraindicated. Weak CYP2C19 Inhibitors or Moderate CYP3A4 Inhibitors : Concomitant use with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor increases CAMZYOS exposure, which may increase the risk of adverse drug reactions. Initiate CAMZYOS at the recommended starting dose of 5 mg orally once daily in patients who are on stable therapy with a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor. Reduce dose of CAMZYOS by one level (ie, 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients who are on CAMZYOS treatment and intend to initiate a weak CYP2C19 inhibitor or a moderate CYP3A4 inhibitor. Schedule clinical and echocardiographic assessment 4 weeks after inhibitor initiation, and do not up-titrate CAMZYOS until 12 weeks after inhibitor initiation. Avoid initiation of concomitant weak CYP2C19 and moderate CYP3A4 inhibitors in patients who are on stable treatment with 2.5 mg of CAMZYOS because a lower dose is not available. For short-term use (eg, 1 week), interrupt CAMZYOS for the duration of treatment with a weak inhibitor of CYP2C19 or a moderate inhibitor of CYP3A4. CAMZYOS may be reinitiated at the previous dose immediately on discontinuation of concomitant therapy. Moderate CYP2C19 Inhibitors or Strong CYP3A4 Inhibitors : Concomitant use with a moderate CYP2C19 inhibitor or strong CYP3A4 inhibitor increases CAMZYOS exposure, which may increase the risk of adverse drug reactions. Discontinuing use of a moderate CYP2C19 inhibitor or strong CYP3A4 inhibitor after long-term concomitant use may decrease CAMZYOS exposure, which may reduce CAMZYOS’ efficacy. Initiate CAMZYOS at a starting dosage of 2.5 mg orally once daily in patients who are on a stable therapy with a moderate CYP2C19 inhibitor or a strong CYP3A4 inhibitor. Reduce dose of CAMZYOS by one level (ie, 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients who are on CAMZYOS and intend to initiate a moderate CYP2C19 inhibitor or a strong CYP3A4 inhibitor. Avoid initiation of concomitant moderate CYP2C19 and strong CYP3A4 inhibitors in patients who are on a stable treatment with 2.5 mg of CAMZYOS because a lower dose is not available. An increase in dose of CAMZYOS may be needed if the moderate inhibitor of CYP2C19 or strong inhibitor of CYP3A4 is discontinued after long-term concomitant use. Monitor for new or worsening symptoms. For short-term use (ie, when CAMZYOS dose modification is not feasible), interrupt CAMZYOS for the duration of treatment with a moderate inhibitor of CYP2C19 or a strong inhibitor of CYP3A4. CAMZYOS may be reinitiated at the previous dose immediately on discontinuation of concomitant therapy. Potential for CAMZYOS to Affect Plasma Concentrations of Other Drugs CAMZYOS is an inducer of CYP3A4, CYP2C9, and CYP2C19. Concomitant use with CYP3A4, CYP2C9, or CYP2C19 substrates may reduce plasma concentration of these drugs. Closely monitor when CAMZYOS is used with concomitant CYP3A4, CYP2C9, or CYP2C19 substrates unless otherwise recommended in the Prescribing Information. Certain Combined Hormonal Contraceptives (CHCs): Progestin and ethinyl estradiol are CYP3A4 substrates. Concomitant use of CAMZYOS may decrease exposures of certain progestins, which may lead to contraceptive failure. CHCs containing a combination of ethinyl estradiol and norethindrone may be used with CAMZYOS, but if other CHCs are used, advise patients to add nonhormonal contraception (such as condoms) or use an alternative contraceptive method that is not affected by CYP450 enzyme induction (eg, intrauterine system) during concomitant use and for 4 months after the last dose of CAMZYOS. Drugs That Reduce Cardiac Contractility Expect additive negative inotropic effects of CAMZYOS and other drugs that reduce cardiac contractility. Avoid concomitant use of CAMZYOS in patients on disopyramide, ranolazine, verapamil with a beta blocker, or diltiazem with a beta blocker as these medications and combinations increase the risk of left ventricular systolic dysfunction and heart failure symptoms and clinical experience is limited. If concomitant therapy with a negative inotrope is initiated, or if the dose of a negative inotrope is increased, monitor LVEF closely until stable doses and clinical response have been achieved. SPECIFIC POPULATIONS Pregnancy Based on animal data, CAMZYOS may cause fetal harm when administered to a pregnant female. Advise pregnant females about the potential risk to the fetus with maternal exposure to CAMZYOS during pregnancy. There is a pregnancy safety study for CAMZYOS. If CAMZYOS is administered during pregnancy, or if a patient becomes pregnant while receiving CAMZYOS or within 4 months after the last dose of CAMZYOS, healthcare providers should report CAMZYOS exposure by contacting Bristol Myers Squibb at 1-800-721-5072 or . Lactation The presence of CAMZYOS in human or animal milk, the drug’s effects on the breastfed infant, or the effects on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CAMZYOS and any potential adverse effects on the breastfed child from CAMZYOS or from the underlying maternal condition. Females and Males of Reproductive Potential Confirm absence of pregnancy in females of reproductive potential prior to initiation of CAMZYOS. Advise females of reproductive potential to use effective contraception during treatment with CAMZYOS and for 4 months after the last dose. CHCs containing a combination of ethinyl estradiol and norethindrone may be used with CAMZYOS. However, CAMZYOS may reduce the effectiveness of certain other CHCs. If these CHCs are used, advise patients to add nonhormonal contraception (such as condoms) or use an alternative contraceptive method during concomitant use and for 4 months after the last dose of CAMZYOS. Please see U.S. Full Prescribing Information , including Boxed WARNING and Medication Guide . About Bristol Myers Squibb: Transforming Patients’ Lives Through Science At Bristol Myers Squibb, our mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. We are pursuing bold science to define what’s possible for the future of medicine and the patients we serve. For more information, visit us at BMS.com and follow us on LinkedIn , X , YouTube , Facebook and Instagram . Cautionary Statement Regarding Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that Camzyos (mavacamten) may not receive regulatory approval for the additional indication described in this release in the currently anticipated timeline or at all, any marketing approvals, if granted, may have significant limitations on their use, and, if approved, whether Camzyos for such additional indication will be commercially successful. No forward-looking statement can be guaranteed. It should be noted that acceptance of the application does not change the standards for FDA approval. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2025, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise. corporatefinancial-news Contacts Bristol Myers Squibb Media Inquiries: media@bms.com Investors: investor.relations@bms.com

点击蓝字 · 关注我们 · 脂代谢紊乱与胰腺疾病专题 · 脂代谢异常与胰腺疾病相关研究进展 戈阳  王洋  孔祥毓  李兆申 海军军医大学第一附属医院消化内科，上海 200433 通信作者：孔祥毓，Email：xiangyukong185@hotmail.com；李兆申，Email：zhsl@vip.163.com 提  要 胰腺疾病是全球范围内高发的消化系统疾病，主要包括急性胰腺炎、慢性胰腺炎和胰腺癌，具有发病率高、病情危重、预后不良的特点，给公共卫生体系带来了巨大压力。近年来，代谢重编程在胰腺疾病发生发展中的关键作用逐渐被揭示，其中脂代谢异常作为关键环节，与胰腺疾病的发病机制、病情进展、预后评估及靶向治疗密切相关。本文系统梳理了脂代谢异常的基本概念和分类，详细分析其与急性胰腺炎、慢性胰腺炎及胰腺癌之间的病理联系，探究靶向脂质代谢干预胰腺疾病的临床应用前景，并总结当前研究的不足及未来的发展方向，以期为胰腺疾病的机制研究、临床诊疗及新药研发提供系统的理论依据与数据支持。 全文刊载于 《中华胰腺病杂志》 2026年 第26卷 第S1期 7-14页 PDF全文请点击下方“阅读原文” 全文阅读 胰腺是兼具外分泌与内分泌功能的重要腺体，其生理功能稳态维系着机体消化吸收与糖脂代谢的正常运转。胰腺疾病是消化系统常见病，其中急性胰腺炎起病急骤、重症患者病死率居高不下；慢性胰腺炎易反复发作，并可进展为胰腺功能衰竭；胰腺癌则因早期诊断困难、恶性程度极高，被称为“癌中之王”。全球流行病学数据显示，胰腺疾病的发病率呈逐年上升趋势，已成为威胁人类健康的重大疾病之一。代谢重编程是指细胞或生物体为适应外部环境刺激或内部生理需求，而对其代谢网络进行系统性、主动且可塑的重构过程。随着代谢医学与肿瘤代谢学的快速发展，越来越多的研究证实，代谢重编程是胰腺疾病发生发展的核心病理特征之一。胰腺组织对脂代谢紊乱高度敏感。脂肪作为机体重要的能量来源、细胞膜组成成分及信号传导分子，其代谢失衡不仅会诱发胰腺组织局部微环境紊乱，还会通过介导炎症反应、氧化应激、细胞凋亡、纤维化形成及肿瘤细胞增殖侵袭等多种通路，参与胰腺疾病发生发展的多个关键环节。相较于糖代谢异常，脂代谢异常与胰腺疾病的关联研究起步较晚。但近年来随着脂质组学、分子生物学技术的迭代更新，脂代谢异常在胰腺疾病中的作用机制逐渐被阐明，靶向脂质代谢的干预策略也成为胰腺疾病诊疗的研究热点。本文系统综述脂代谢异常在胰腺疾病中的作用机制，并探讨相关诊断标志物与治疗策略，以期为胰腺疾病的临床诊治提供参考。 一、脂代谢异常的定义与分类 脂质是一类不溶于水、易溶于有机溶剂的生物分子，主要包括甘油三酯（triglyceride，TG）、胆固醇、磷脂、游离脂肪酸及其衍生物，是生物膜的重要结构成分，参与激素合成、能量储备与细胞信号转导。脂质代谢是指机体脂质的吸收、合成、分解、转运及储存过程，其稳态依赖于关键酶与核受体的精准调控，并受基因、饮食、激素及肠道菌群等多重因素影响。脂代谢异常是指由于脂质代谢紊乱，导致血浆、组织间液及细胞内脂质浓度与比例失衡的代谢性疾病，是代谢综合征、心血管疾病、非酒精性脂肪性肝病等多种疾病的共同病理基础。依据《中国血脂管理指南（2023年）》，临床将脂代谢异常分为高胆固醇血症、高甘油三酯血症、混合型高脂血症及低高密度脂蛋白胆固醇血症4类。高胆固醇血症以总胆固醇（total cholesterol，TC）≥6.2 mmol/L为诊断界值；高甘油三酯血症以空腹TG≥2.26 mmol/L为诊断界值，重度升高（≥5.65 mmol/L）是急性胰腺炎的独立危险因素；低高密度脂蛋白胆固醇血症（男性1.0 mmol/L、女性1.3 mmol/L）提示机体逆向胆固醇转运能力下降，常与其他脂代谢异常并存。此外，低密度脂蛋白胆固醇（low density lipoprotein cholesterol，LDL-C）3.4 mmol/L时提示胆固醇合成与清除失衡，血浆胆固醇负荷增加；氧化型低密度脂蛋白增多、脂质过氧化产物堆积等脂质成分异常，可通过介导氧化应激与炎症反应损伤组织细胞。 二、脂代谢异常与胰腺疾病 胰腺组织富含脂质代谢相关酶类，且对游离脂肪酸、脂质过氧化产物高度敏感。脂代谢异常可通过炎症级联反应、胰腺纤维化、代谢重编程等途径，诱发或加重多种胰腺疾病。目前研究表明，脂代谢异常与急性胰腺炎、慢性胰腺炎及胰腺癌均存在不同程度的关联，且上述疾病在发展过程中又可进一步加剧脂代谢紊乱，形成恶性循环。 1.脂代谢异常与急性胰腺炎：急性胰腺炎是胰酶异常激活引发的胰腺局部急性炎症反应。重症患者可进展为多器官功能衰竭，病死率高达30%~40%。常见病因包括胆源性、高甘油三酯血症性和酒精性。在我国，高甘油三酯血症已超过酒精成为急性胰腺炎的第二大病因，且发病率逐年上升，占急性胰腺炎总发病率的12%~20%，在重症患者中比例更高。高甘油三酯血症诱发急性胰腺炎的核心机制如下：其一，过量TG经胰腺脂肪酶水解，产生大量游离脂肪酸。游离脂肪酸与钙离子结合形成脂肪酸钙盐沉积，损伤胰腺腺泡细胞膜，破坏细胞完整性。受损的细胞进一步释放胰腺脂肪酶，持续水解TG，使游离脂肪酸不断蓄积，对腺泡细胞及胰腺毛细血管造成持续毒性损伤，并进一步促进胰腺脂肪酶释放。游离脂肪酸还可诱导腺泡细胞内钙超载，损伤线粒体功能，进而触发胰蛋白酶原异常激活，启动胰腺自消化过程。Wang等发现，高甘油三酯血症小鼠经雨蛙素诱导后，胰腺出血、坏死程度比野生型小鼠更重，血清淀粉酶水平也更高。离体细胞实验进一步表明，胰腺脂肪酶可水解乳糜微粒生成游离脂肪酸，诱发腺泡细胞内钙离子浓度持续性升高，直接导致细胞损伤。其二，通过激活NOD样受体蛋白3（NOD-like receptor pyrin domain containing 3，NLRP3）炎症小体和NF-κB通路，游离脂肪酸可促进IL-1β、TNF-α等炎症因子大量释放，触发炎症级联反应，加重胰腺组织水肿、坏死。其三，血液中富含TG的脂蛋白颗粒增多，导致血液黏稠度升高、血流阻力增大，引起胰腺血流灌注受损与微循环障碍，缺血缺氧进一步加剧腺泡细胞损伤。其四，脂质过氧化产物堆积诱发氧化应激，使胰腺组织抗氧化与促氧化失衡，直接损伤腺泡细胞并激活细胞凋亡通路；此外，线粒体受损后释放的损伤相关分子模式可进一步放大炎症反应，加速胰腺组织坏死。上述多重机制共同驱动胰腺损伤的持续进展，且其损伤程度与TG水平密切相关。研究证实，血浆TG水平越高，急性胰腺炎发病风险、重症转化率及病死率越高；当TG11.3 mmol/L时，急性胰腺炎发病风险显著升高。 除高甘油三酯血症外，其他脂代谢异常同样与急性胰腺炎的发生和严重程度密切相关。低密度脂蛋白胆固醇和总胆固醇均与急性胰腺炎严重程度呈U型关联，过低或过高均会增加重症急性胰腺炎风险。低水平低密度脂蛋白胆固醇提示机体炎症应激过度、合成不足；高水平则通过氧化应激和微循环障碍加重胰腺损伤。与此不同，高密度脂蛋白胆固醇在急性胰腺炎早期即显著降低，其水平与病情严重程度、持续性器官功能衰竭呈负相关。低水平高密度脂蛋白胆固醇因其抗炎、抗氧化及促进胆固醇逆向转运功能受损，可加剧胰腺坏死与多器官功能障碍的进展。但目前机制证据仍以动物实验为主，临床因果关系尚不完全明确。此外，脂肪胰作为脂代谢异常的局部表现，可使胰腺组织对炎症刺激更敏感，进而增加急性胰腺炎复发风险。 2.脂代谢异常与慢性胰腺炎：脂代谢异常与慢性胰腺炎之间存在双向作用，脂代谢异常可驱动胰腺纤维化进展，慢性胰腺炎本身也能加重脂质代谢紊乱，二者相互影响。过量TG及其代谢产物与胰腺纤维化的进展密切相关，但两者之间的因果关系尚存争议。长期脂代谢异常可导致血浆游离脂肪酸水平持续升高，游离脂肪酸作为重要的脂毒性介质，可直接损伤胰腺腺泡细胞，诱发慢性低度炎症反应。持续的炎症信号进而激活作为胰腺纤维化核心效应细胞的胰腺星状细胞，促使其大量分泌胶原蛋白及细胞外基质，最终加速胰腺纤维化进程。Sun等和Yang等通过单细胞核糖核酸测序发现，慢性胰腺炎中存在具有高脂质代谢活性的极低密度脂蛋白受体阳性胰腺星状细胞亚群，该亚群可摄取极低密度脂蛋白并促进胞内TG蓄积，进而诱导IL-33表达与释放，激活胰腺2型固有淋巴细胞，后者通过分泌IL-13等细胞因子进一步促进胰腺星状细胞活化，参与胰腺纤维化进展。 反之，慢性胰腺炎也会引起胰腺内外分泌功能双重受累。外分泌功能不足致使脂肪酶的分泌量下降，造成肠道脂肪消化吸收障碍，进而引发脂肪泻及脂溶性维生素缺乏；内分泌功能受损则导致胰岛素分泌不足，进一步干扰脂质代谢稳态。然而，由于此类患者常合并肠道吸收障碍和营养不良，血浆TG水平并不必然升高，临床上易被忽视。 3.脂代谢异常与胰腺癌：胰腺癌是恶性程度极高的消化道肿瘤，代谢重编程是其核心生物学特征，其中脂质代谢异常贯穿胰腺癌发生、发展、侵袭转移及耐药全过程。胰腺癌组织发生了以KRAS突变为核心驱动的系统性脂质代谢重塑，不仅为肿瘤细胞快速增殖提供能量与结构物质，还参与了胰腺癌免疫抑制性肿瘤微环境的塑造。 （1）脂代谢异常驱动胰腺癌进展的机制。长期脂质代谢异常（尤其肥胖、高胆固醇血症、游离脂肪酸过量）可诱导胰腺组织慢性炎症、氧化应激与脱氧核糖核酸损伤，激活促癌通路、下调抑癌基因，驱动胰腺导管上皮异型增生并恶性进展为胰腺癌。流行病学研究证实，肥胖、高甘油三酯血症、高胆固醇血症是胰腺癌的独立危险因素，身体质量指数（body mass index，BMI）每升高5 kg/m²，胰腺癌发病风险增加10%~15%。胰岛素抵抗介导的高胰岛素血症则可通过胰岛素样生长因子通路促进胰腺癌细胞增殖，加速肿瘤进展。胰腺癌细胞可通过异常调控脂质摄取、合成与分解代谢，满足其恶性增殖与侵袭的能量及物质需求。 胰腺癌脂质代谢重编程由遗传与环境因素协同驱动。遗传层面，KRAS突变通过持续激活磷脂酰肌醇-3-激酶（phosphatidylinositol 3-kinase，PI3K）/蛋白激酶B（protein kinase B，AKT）/哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）与丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）通路，促进脂质合成核心转录因子固醇调节元件结合蛋白（sterol regulatory element-binding protein，SREBP）1/2核转位。其中SREBP1直接上调乙酰辅酶A羧化酶、脂肪酸合成酶、硬脂酰辅酶A去饱和酶1（stearoyl-CoA desaturase 1，SCD1）等脂肪酸合成关键酶表达，从而启动脂质合成；SREBP2则通过调控3-羟基-3-甲基戊二酰辅酶A还原酶（3-hydroxy-3-methylglutaryl-coenzyme A reductase，HMGCR）、低密度脂蛋白受体等靶基因介导甲羟戊酸通路激活。环境层面，肥胖是胰腺癌发生的独立危险因素且与不良预后相关。高脂饮食可增强KRAS突变癌细胞的脂肪酸β-氧化活性、促进腺嘌呤核苷三磷酸（adenosine triphosphate，ATP）生成以驱动肿瘤生长，该效应可被脂肪酸氧化（fatty acid oxidation，FAO）关键转运蛋白溶质载体家族成员20抑制剂逆转；肿瘤微环境中，肿瘤相关巨噬细胞亦可通过信号转导与转录激活因子3-泛素特异性肽酶20轴强化KRAS驱动的代谢重编程，促进胰腺癌进展。 KRAS-SREBP轴驱动胰腺癌细胞发生系统性脂质代谢重编程，其核心特征包括：①脂肪酸从头合成通路显著上调，癌症基因组图谱（cancer genome atlas，TCGA）-胰腺导管腺癌（pancreatic ductal adenocarcinoma，PDAC）代谢模型显示，超过62%的脂肪酸及胆固醇合成相关反应上调（平均幅度为1.5倍），涉及ATP柠檬酸裂解酶、FASN等。此外，KRAS突变的PDAC细胞还可通过靶向脂肪酸转位酶CD36摄取外源性脂肪酸。②甲羟戊酸通路过度激活，HMGCR表达上调，其下游产物胆固醇可驱动KRAS突变背景下的关键癌前事件——腺泡导管组织转化的发生。另一产物牻牛儿基焦磷酸则通过GG化修饰RHO/RAL小GTPase，驱动肿瘤增殖。③脂滴调控异常介导铁死亡抵抗。SCD1上调可调控膜脂饱和度；KRAS突变还可抑制激素敏感性脂肪酶，促进脂滴蓄积，二者共同构成铁死亡抵抗屏障。 （2）胰腺癌脂质代谢重塑与免疫微环境的内在联系。胰腺癌脂质代谢重塑与免疫微环境塑造密切相关，是肿瘤进展、免疫逃逸及治疗耐受的核心机制之一。Tiberti等研究表明，胰腺微环境中肿瘤细胞异常合成并大量积聚的长链脂肪酸（如棕榈酸），经CD36介导进入浸润性CD8⁺T细胞后，未作为能量底物参与脂肪酸氧化反应，反而通过损伤线粒体完整性（膜电位下降、mtDNA释放增加及活性氧过量累积），并下调肉碱棕榈酰转移酶1A等脂肪酸分解关键酶的表达以阻断脂肪酸氧化进程，最终导致CD8⁺T细胞颗粒酶B、穿孔素等效应分子分泌减少，细胞毒功能进行性丧失并形成耗竭表型。该研究证实，脂质介导的CD8⁺T细胞功能损伤可显著削弱机体抗肿瘤免疫应答，为肿瘤细胞免疫逃逸创造条件。 此外，多种免疫抑制性细胞可通过调节上述信号通路影响脂质代谢，共同加剧胰腺肿瘤微环境的免疫抑制状态。Song等研究发现，调节性T细胞（regulatory T cell，Treg）在胰腺癌乏氧、营养受限的微环境中，可上调脂肪酸氧化与线粒体氧化磷酸化供能；Xiang等的研究进一步证实，Treg可借助哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTORC1）-HMGCR-鲨烯环氧酶（squalene epoxidase，SQLE）轴激活脂质合成通路，促进胆固醇及脂质生成，进而上调核心抑制标志物与免疫检查点分子表达，持续发挥免疫抑制作用。Parejo-Alonso等研究表明，肿瘤相关巨噬细胞（tumor-associated macrophage，TAM）可有效摄取微环境游离脂肪酸与氧化型低密度脂蛋白，经PPARδ/β-catenin通路驱动脂肪酸氧化并向M2型极化。Xiao等指出，胆固醇代谢酶CH25H介导的25-羟基胆固醇积累，可促进M2型TAM分泌抑炎因子及精氨酸酶1，进一步抑制抗肿瘤免疫。Tang等研究显示，SCD1异常表达可通过促进单不饱和脂肪酸合成、激活Nrf2抗氧化通路，减少髓系来源抑制性细胞的脂质过氧化损伤，维持其存活与免疫抑制功能。Qin等的研究表明，胰腺癌细胞与上述免疫抑制细胞的代谢重编程存在紧密交互并形成代谢共生环路。Wu等进一步证实，CD36、肉碱棕榈酰转移酶1A（carnitine palmitoyltransferase 1A，CPT1A）、SCD1等脂质代谢关键分子作为核心纽带，串联肿瘤细胞与免疫细胞的代谢网络，共同构建高度免疫抑制微环境，最终导致胰腺癌对免疫检查点抑制剂产生耐药性。 三、靶向脂质代谢在胰腺疾病治疗中的作用 高脂血症性急性胰腺炎的核心治疗目标是快速降低血浆TG浓度并阻断FFA引发的脂毒性，临床现已形成从急性期常规干预到远期分子靶向治疗的多维度分层干预体系。 1.急性胰腺炎的靶向脂质代谢治疗：所有药物干预前，需优先识别并纠正未控制的2型糖尿病、甲状腺功能减退、药物因素及大量饮酒等继发性病因，同时严格禁食；消除驱动因素即可使TG快速下降。急性抢救期，血浆置换与连续性血液净化可快速清除循环中过量TG及炎症介质，但2023年美国血浆置换学会指南指出，其用于重症高甘油三酯血症性急性胰腺炎需综合评估、个体化选择，并非标准一线治疗。静脉泵入胰岛素是急性期降脂的常用药物方案，可通过激活内源性脂蛋白脂肪酶（lipoprotein lipase，LPL）加速TG水解。目前指南推荐较为保守，证据多来自小样本观察性研究，需个体化应用。低分子肝素可将内皮表面LPL释放入血浆以短暂加速TG水解，但持续输注会导致LPL耗竭，引发血脂反弹并增加重症出血风险，需与其他降脂药联用。当前证据不支持常规联用肝素，指南亦未明确禁止，临床决策需个体化。近期He等的多中心RCT证实，低分子肝素联合胰岛素在减少新发器官功能衰竭或死亡率方面不优于单纯胰岛素治疗。恢复期以极低脂饮食配合贝特类药物为核心，联合处方级ω-3脂肪酸或他汀类药物，是控制血脂及预防复发的基础方案。贝特类药物通过激活过氧化物酶体增殖物激活受体α（peroxisome proliferator-activated receptor alpha，PPARα），提高LPL活性，减少载脂蛋白C-Ⅲ合成，从而实现降脂。 2.慢性胰腺炎的靶向脂质代谢治疗：慢性胰腺炎的脂质代谢干预以纠正外分泌功能不全、防治营养素缺乏为核心。在饮食方面，一般慢性胰腺炎患者应避免常规低脂饮食，以防加重能量负平衡，亦不推荐高膳食纤维饮食。对于合并高甘油三酯血症的患者，应严格限制长链脂肪摄入，同时限制精制碳水化合物及酒精，其脂质代谢相关干预原则与急性胰腺炎基本一致。外源性胰酶替代治疗（pancreatic enzyme replacement therapy，PERT）是治疗胰腺外分泌功能不全的主要方式。PERT即口服肠溶包衣胰酶制剂，随餐补充分泌不足的消化酶，从而改善营养物质消化吸收。系统文献综述显示，PERT可有效改善胰腺外分泌功能不全患者的脂肪及氮吸收功能，调节体重及BMI，且安全性与耐受性良好。若足量PERT仍无法控制脂肪吸收障碍时，可引入中链TG替代部分膳食脂肪。脂肪吸收障碍还涉及广泛的微量营养素失衡，维生素A、D、E、K因依赖脂质载体吸收而普遍缺乏，应定期监测血清水平并针对性补充。 3.胰腺癌的靶向脂质代谢治疗：胰腺癌靶向脂质代谢治疗是当前克服化疗耐药、改善免疫抑制微环境的研究热点。在脂肪酸代谢层面，针对从头合成通路的FASN抑制剂临床前研究中可与化疗产生协同抗癌效应，其中FASN抑制剂（denifanstat-2640，TVB-2640）已在多种实体瘤中进入临床试验。在FASN上游，针对ATP-ACLY或ACC的抑制剂（如Bempedoic acid、BAY ACC002）也能显著抑制PDAC细胞生长，但需警惕脂代谢相关的代偿性反馈激活。同时，PDAC细胞高度依赖线粒体脂肪酸氧化供能，FAO抑制剂（如Ranolazine）与吉西他滨联用在患者来源异种移植模型中，可在一定程度上延缓肿瘤生长并降低癌症干细胞比例。Etomoxir作为CPT1不可逆抑制剂，在临床前研究中亦观察到类似效果，但其高浓度下存在脱靶效应及肝毒性风险。此外，阻断CD36介导的外源性脂质摄取，以及应用二酰基甘油酰基转移酶（diacylglycerol acyltransferase，DGAT）抑制剂阻断脂滴合成诱发脂毒性，是阻断PDAC脂质利用的前沿策略。在胆固醇代谢层面，他汀类药物通过阻断甲羟戊酸通路，可改善PDAC患者生存，尤其是手术切除后患者。而乙酰辅酶A乙酰转移1抑制剂Avasimibe可通过阻断胆固醇酯化，抑制胰腺癌生长与转移，并协同吉西他滨克服耐药，但其疗效与安全性尚需人体临床试验验证。铁死亡为胰腺癌治疗提供了机制合理的新思路。临床前研究显示，抑制GPX4活性或阻断胱氨酸/谷氨酸反向转运体介导的胱氨酸摄取，均可诱导脂质过氧化蓄积，触发胰腺癌细胞铁死亡；上调酰基辅酶A合成酶长链家族成员4可增强细胞对铁死亡的敏感性，调控铁稳态可进一步协同增强杀伤效应。该策略在克服凋亡耐药与化疗增敏方面展现出初步潜力，但仍需深入验证。未来基于脂质代谢抑制剂与标准化疗、免疫治疗或铁死亡诱导剂的多靶点联合干预，是推动PDAC脂质代谢治疗临床转化的核心关键。 4.靶向脂质代谢治疗的局限性与优化方向：目前靶向脂质代谢治疗仍存在靶点特异性不足、不良反应显著、单一干预模式临床疗效有限等瓶颈问题。未来需研发高选择性靶向药物，联合代谢干预、免疫治疗等多模式综合策略，实现胰腺疾病精准、安全的代谢靶向治疗。 四、结论与展望 综上所述，脂代谢异常与胰腺疾病存在密不可分的双向关联，其作为重要的致病因素、病情驱动因子及治疗靶点，贯穿于急性胰腺炎、慢性胰腺炎、胰腺癌的全病程。脂代谢异常通过脂毒性、炎症激活、氧化应激、纤维化形成及代谢重塑等多种机制，参与胰腺疾病的发生发展。脂质组学技术的发展为胰腺疾病的早期诊断与病情监测提供了特异性标志物，而靶向脂质代谢的干预策略则为胰腺疾病治疗开辟了全新路径，展现出广阔的临床应用前景。 尽管现有研究已初步阐明脂代谢异常与胰腺疾病的关联机制，但仍存在诸多不足：脂代谢异常介导胰腺疾病的分子网络尚未完全明晰；不同类型胰腺疾病的脂质代谢特征差异有待深入挖掘；脂质组学标志物的临床标准化检测流程亟待建立；靶向脂质代谢药物的安全性与有效性仍需大样本临床试验验证。 未来研究方向应聚焦以下几点：一是深入解析脂代谢与胰腺疾病的分子调控网络，挖掘关键靶点与信号通路；二是开展大规模临床脂质组学研究，筛选高特异性、高灵敏度的胰腺疾病诊断标志物；三是研发高选择性、低毒性的靶向脂质代谢药物，并推动其临床转化；四是建立胰腺疾病代谢分层管理体系，以实现早期筛查、精准干预与个体化治疗。相信随着代谢医学、分子生物学及脂质组学技术的不断突破，脂代谢异常与胰腺疾病相关研究将取得更大进展，为攻克胰腺疾病提供坚实的理论与实践支撑。 引用本文 戈阳, 王洋, 孔祥毓, 等. 脂代谢异常与胰腺疾病相关研究进展[J]. 中华胰腺病杂志, 2026, 26(S1): 7-14. DOI: 10.3760/cma.j.cn115667-20260324-00066.  波科国际医疗贸易（上海）有限公司 微信号CJP-2001 长按二维码关注我们 《中华胰腺病杂志》