Arresting idiopathic pulmonary fibrosis progression: EZY-1 targets mTORC2 to inhibit senescence-associated secretory phenotype

EZY-1, a bioactive compound derived from the edible seaweed Eucheuma, was identified as a potent and selective mechanistic target of rapamycin complex 2 (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 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 the senescence-associated β-galactosidase (SA-β-gal) activity, decreasing the secretion of senescence-associated secretory phenotype factors. EZY-1 also restored G1/S phase cell cycle progression by upregulating cyclin-dependent kinase 4 (CDK4) and CDK2 levels. These molecular responses substantially suppress epithelial-mesenchymal transition 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 via its multi-target role against core fibrotic mechanisms.