Arresting IPF Progression: EZY-1 Targets mTORC2 to Inhibit Senescence-Associated Secretory Phenotype (SASP)

EZY-1, a bioactive compound derived from the edible seaweed Eucheuma, was identified as a potent and selective mTORC2 inhibitor. This agent showed significant anti-fibrotic efficacy in a bleomycin-induced pulmonary fibrosis model by targeting multiple pathological pathways. Treatment with EZY-1 significantly reduced extracellular matrix (ECM) deposition, as confirmed by reduced collagen accumulation and suppressed expression of fibrosis-associated markers. EZY-1 attenuated cellular senescence by downregulating senescence indicators such as p53, p27, p21, p16, and SA-β-gal activity, decreasing the secretion of senescence-associated secretory phenotype (SASP) factors. EZY-1 also restored G1/S phase cell cycle progression by upregulating cyclin-dependent kinases CDK4 and CDK2 levels. These molecular responses substantially suppress epithelial-mesenchymal transition (EMT) and fibroblast activation. Mechanistic studies revealed that the anti-fibrotic effect of EZY- 1 is primarily mediated through suppression of the mTORC2/PI3K/Akt signaling cascade, modulating the mTORC2→Akt→p53/p21→CDK4/2 axis. In vitro analyses confirmed these effects on mTORC2 inhibition. These findings propose EZY-1 as a promising therapeutic candidate for treating idiopathic pulmonary fibrosis (IPF) via its multi-target role against core fibrotic mechanisms.