Colorectal cancer chemotherapy faces challenges with low intratumoral drug accumulation and off-target toxicity. Micellar liposome complex carriers are a promising anti-cancer platform due to their high encapsulation efficiency, responsive release, and multi-targeting capabilities. This study explores a novel tumor-targeted chemotherapy approach by encapsulating GSH/NQO1-responsive SN38 prodrug micelles into cholesterol-replacement multifunctional liposomes. Timosaponin AIII (TAIII), a steroid saponin with anticancer activity, substitutes cholesterol to stabilize liposomes, benefiting from its steroidal aglycone structure. Additionally, TAIII mimics PEGylation via its glucose moiety, enhancing tumor targeting via the overexpression of glucose transporter 1 (GLUT1) on cancer cells. Molecular docking studies with AutoDock revealed that GLUT1 residues stabilize TAIII in the binding pocket through hydrogen bonding, hydrophobic, and polar interactions, promoting its transmembrane transport. A specific amphiphilic SN38 prodrug, PEG-SS-SN38-QPA (PSSQ), was synthesized and self-assembled into micelles via a solvent injection-dialysis method for GSH/NQO1-responsive controlled drug release in the tumor microenvironment. PSSQ micelles were integrated into the hydrophilic cavity of TAIII-based liposomes (TLP, prepared by the thin-film hydration method) through passive encapsulation to form PSSQ@TLP. In vitro release study exhibiting GSH/NQO1-triggered release under simulated tumor microenvironment. In vitro cytotoxicity evaluation was performed using the MTT assay on HCT116, LOVO, CT26.WT cell lines. Following in vivo evaluations of biodistribution, anti-tumor efficacy, and biosafety in CT26.WT xenograft tumor-bearing mice, PSSQ@TLP demonstrated enhanced intratumoral accumulation, robust tumor suppression, and minimized systemic toxicity, underscoring its promise as a targeted therapeutic strategy for colorectal cancer.

2026-04-01·FREE RADICAL BIOLOGY AND MEDICINE

FGF2-targeted Timosaponin AIII provokes ER stress and dampens PI3KAKT signaling pathway in breast cancer

Article

作者: Li, Zilin ; Zhang, Zhe ; Qian, Xiaoqin

Timosaponin AIII (Tim-AIII), a steroidal saponin derived from Anemarrhena asphodeloides, has emerged as a promising antitumor agent, yet its precise molecular targets and mechanisms in breast cancer remain poorly defined. Here, we identify fibroblast growth factor 2 (FGF2) as a direct binding target of Tim-AIII using a combination of network pharmacology, CETSA, and surface plasmon resonance assays. Mechanistically, Tim-AIII exhibits a dual therapeutic mode of action. First, it induces reactive oxygen species (ROS)-mediated endoplasmic reticulum (ER) stress, activating the eIF2α-ATF4-CHOP axis and initiating apoptosis. Second, it dampens the FGF2-FGFR1-PI3K/AKT signaling cascade, thereby inhibiting epithelial-mesenchymal transition (EMT) and suppressing cell migration and invasion. RNA sequencing and enrichment analyses confirm that Tim-AIII regulates critical oncogenic pathways, including ER stress, calcium signaling, and PI3K/AKT. In vivo evaluations demonstrate that Tim-AIII significantly reduces tumor growth without detectable systemic toxicity in breast cancer-bearing mice. This study not only elucidates the molecular basis of Tim-AIII's antitumor efficacy but also positions it as a potential targeted therapeutic for breast cancer, with dual action on ERS-induced apoptosis and EMT suppression.

2025-12-01·INTERNATIONAL IMMUNOPHARMACOLOGY

Timosaponin AIII from Anemarrhena asphodeloides binds and inhibits S100A8-mediated neutrophil infiltration and NET formation ameliorates MASH

Article

作者: Lan, Xintian ; Luo, Haoming ; Zhu, Ming ; Fang, Xiaoxue ; Zhao, Xinyi ; Li, Jing ; Ju, Jingxin ; Bai, Yunfan ; Xie, Ruishi

OBJECTIVE:

This study aimed to identify the active compound from Anemarrhena asphodeloides Bge. (AA) that ameliorates metabolic dysfunction-associated steatohepatitis (MASH) and to elucidate its mechanism of action.

METHODS:

A screening was conducted using a high-cholesterol diet-induced zebrafish MASH model. The active ingredients and compounds were subsequently evaluated in a feed-induced mice model of methionine-choline deficiency (MCD) and a primary neutrophil model induced by PMA. Immune cell depletion, network pharmacology, transcriptomics, molecular docking, and surface plasmon resonance (SPR) were utilized to identify targets and pathways.

RESULTS:

Timosaponin AIII (TA3) from AA n-butanol extract could significantly improve the pathological characteristics of MASH. In mice, TA3 reduced lipid accumulation, liver injury, inflammation, and neutrophil infiltration. Neutrophil depletion studies confirmed that TA3 primarily acts by targeting neutrophils. It inhibited neutrophil extracellular trap (NET) formation, an effect validated in PAD4-/- mice. Integrated analyses identified S100A8 as a key target; TA3 bound directly to S100A8, disrupting the S100A8/A9 heterodimer and subsequently inhibiting the TLR4/NF-κB pathway and reducing ROS production. These effects were abolished upon S100A8 knockdown.

CONCLUSION:

TA3's ability to ameliorate MASH may be associated with the binding of S100A8, which attenuates NETosis and neutrophil infiltration, and inhibits the activation of the TLR4/NF-κB pathway and ROS production.

100 项与 Timosaponin AIII 相关的药物交易

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