Autophagy‐Controlled Collagen I Metabolism and
ECM
Homeostasis: From Molecular Mechanisms to Fibrotic Dysregulation and Therapy
Yuanyuan Liu, Lingwei Wang, Shuyu Chen, Shanze Chen, Bingxin Guo, Wenshan Zhong, Kai Yang, Chao Fang, Rongchang Chen ABSTRACT
Fibrotic diseases are characterized by persistent extracellular matrix (ECM) remodeling and excessive accumulation of fibrillar collagens, particularly Type I collagen (Col I), which collectively drive tissue stiffening, architectural distortion, and progressive organ dysfunction. However, pathological Col I dysregulation is not limited to overproduction or deposition; it may also involve defective folding, impaired trafficking, abnormal secretion, insufficient degradation, or altered collagen availability in specific disease contexts. Emerging evidence identifies autophagy as a central regulator of this network. Beyond its canonical degradative function, autophagy integrates procollagen quality control, endoplasmic reticulum (ER) stress adaptation, selective ER‐phagy, and lysosome‐dependent collagen turnover. Among these processes, selective ER‐phagy eliminates misfolded or surplus procollagen, whereas secretory autophagy and lysosomal turnover determine whether collagen is exported, retained, or degraded. In fibrotic disease, impaired ER‐phagy, maladaptive secretory autophagy, and defective lysosomal flux collectively promote ER stress, aberrant collagen secretion, ECM accumulation, and matrix stiffening. This review summarizes current understanding of the autophagy‐Col I axis across the collagen lifecycle, discusses how its dysregulation contributes to fibrotic remodeling, and highlights checkpoint‐focused therapeutic strategies aimed at restoring collagen clearance and ECM homeostasis.