Senescence-Driven Remodeling Defines an Aggressive and Immunomodulatory Subtype of Endometriosis

Endometriosis is a benign yet invasive disease characterized by ectopic endometrial growth and immune remodeling. While emerging evidence implicates cellular senescence in disease progression, the underlying mechanisms remain largely undefined. In this study, we identified marked heterogeneity in senescence across ectopic lesions and observed that P21-activated kinase 4 (PAK4) was consistently upregulated in senescent cells. Mechanistically, senescence induced PAK4 expression, which in turn interacted with AKT and enhanced its phosphorylation, thereby activating the PI3K/AKT signaling pathway and further amplifying the senescence phenotype. This senescence-PAK4-AKT positive feedback loop ultimately promoted lesion aggressiveness and M2 macrophage polarization. Silencing PAK4 alleviated cellular senescence, attenuated lesion invasiveness, and suppressed immune remodeling. Notably, stigmasterol, a natural phytosterol, effectively downregulated PAK4 expression, disrupted the senescence-AKT feedback loop, and consequently inhibited senescence, invasion, and M2 polarization both in vitro and in vivo. Together, our findings establish a senescence-driven PAK4/AKT signaling circuit that fosters an aggressive, immunomodulatory endometriosis subtype and identify stigmasterol as a promising senescence-targeted therapeutic agent.