Peritoneal metastasis (PM) significantly contributes to the high mortality rate in patients with advanced gastric cancer (GC) and indicates a poor prognosis. A hallmark of cancer is dysregulated lipid metabolism, and gastric cancer peritoneal metastasis (GCPM) is specifically associated with these metabolic alterations. While fatty acid binding protein 4 (FABP4) is a known crucial regulator of fatty acid metabolism in tumor cells, its precise role in GCPM remains unclear. In this study, we found that adipocytes induced FABP4 upregulation in GC cells through PPARγ-dependent signaling, and FABP4 was highly expressed in PM tissues from GCPM patients. FABP4 cooperated with CD36 to facilitate adipocyte-derived arachidonic acid (AA) acquisition while simultaneously limiting the peroxidation of AA that drives ferroptosis. Mechanistically, FABP4 stabilized UBR4 by limiting its lysosome-dependent degradation, thereby promoting UBR4-mediated ubiquitination and degradation of ALOX15, suppressing AA peroxidation and ferroptosis. Collectively, our findings reveal a FABP4-UBR4-ALOX15 axis that links adipocyte-derived lipid metabolism to ferroptosis resistance and peritoneal metastasis in GC cells, and identify FABP4 as a potential therapeutic target for GCPM.
Chemotherapy-induced ovarian injury poses a significant reproductive health challenge for young female cancer survivors, frequently resulting in premature ovarian insufficiency (POI) and infertility. This study demonstrates that menstrual blood-derived endometrial stem cells (MenSCs) and their conditioned secretome (MenSC-S) effectively ameliorate cisplatin-induced ovarian atrophy and functional decline, restoring primordial and growing follicle reserves and rescuing the expression of key functional biomarkers, including anti-Müllerian hormone (AMH), follicle-stimulating hormone receptor (FSHR), estrogen receptor alpha (ERα), and aromatase (Cyp19a1). Mechanistically, we show that chemotherapy induces a pathological shift toward necroptosis in ovarian granulosa cells (GCs) through activation of the RIPK1/RIPK3/p-MLKL signaling cascade, concomitant with suppression of the endogenous necroptosis inhibitor caspase8. We identify heat shock protein family A member 8 (HSPA8) as an indispensable paracrine mediator within MenSC-S that directly interacts with ATR-interacting protein (ATRIP) to establish a previously unrecognized regulatory axis. This physical HSPA8-ATRIP interaction is associated with reduced intracellular reactive oxygen species (ROS) accumulation and restoration of caspase8–mediated inhibition of necroptosis, thereby attenuating the necroptotic signaling cascade. Collectively, our findings support a cell-free therapeutic strategy that achieves efficacy comparable to MenSCs transplantation while offering enhanced biosafety and manufacturing standardization, thereby providing a robust theoretical and experimental foundation for the clinical translation of MenSC-based interventions in oncofertility.
