Chaperone-mediated autophagy coordinates regeneration and fibrosis resolution.

Fibrosis is increasingly viewed as a consequence of defective tissue regeneration rather than simply excessive extracellular matrix accumulation. However, the mechanisms that simultaneously regulate fibroblast activation and regenerative capacity remain poorly understood. In our recent study, we identify chaperone-mediated autophagy (CMA) as a conserved regulator of fibrosis across the lung, liver, and kidney. The CMA receptor lysosome-associated membrane protein 2 (LAMP2A) is consistently downregulated in experimental and human fibrotic diseases, accompanied by reduced CMA activity. Restoration of LAMP2A expression or pharmacological activation of CMA suppresses fibroblast activation through degradation of the mechanosensitive protein integrin subunit beta 1 (ITGB1) and simultaneously enhances regenerative programs in alveolar epithelial cells, hepatocytes, and renal tubular cells. These findings suggest that CMA functions as a regenerative checkpoint that coordinates tissue repair outcomes. Beyond its established role in proteostasis, CMA may determine whether injured tissues undergo successful regeneration or progress toward fibrosis, highlighting CMA activation as a potential therapeutic strategy for chronic fibrotic diseases.Abbreviation: CMA: chaperone-mediated autophagy ITGB1: integrin subunit beta 1 LAMP2A: lysosome associated membrane protein 2.