Targeting the senescence‒autophagy axis via p16INK4a inhibition alleviates pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease for which effective therapies are lacking. While cellular senescence and autophagy have been implicated in IPF pathogenesis, the intersecting mechanisms that drive fibrosis progression remain unclear. Our patient-derived transcriptomic analysis revealed a strong association between enhanced extracellular matrix remodeling, cellular senescence, and autophagic dysfunction in IPF. Among the potential driver genes associated with cellular senescence, the elevated expression of p16INK4A (p16) is correlated with impaired autophagic flux in naturally aging mice, bleomycin (BLM)- and radiation-induced pulmonary fibrosis (PF) mouse models, and lung tissues from IPF patients. Genetic depletion of p16 reduced PF and preserved autophagic flux in response to fibrotic challenge, independent of p21Cip1. Applying this knowledge, we screened antifibrotic compounds from extracts of the medicinal fruit of Melia azedarach and identified toosendanin. This compound suppressed p16 promoter activity, effectively restored autophagic flux, and attenuated BLM-induced PF in vivo. We further showed that the p16 promoter inhibitor abyssinone II alleviated both autophagy dysfunction and fibrosis progression, whereas the promoter activator neorautenol exacerbated both phenotypes, demonstrating that p16 acts as a key regulatory node in the regulation of the crosstalk between senescence and autophagy dysfunction. Collectively, our results identify p16 as a mechanistically defined regulator of fibrosis progression and suggest that modulating this axis may offer new opportunities for therapeutic intervention in IPF. © The Author(s) 2026.