Metformin alleviates ribociclib-induced lung injury by restoring impaired autophagy via targeting Mucolipin-1.

Ribociclib, a cornerstone CDK4/6 inhibitor for advanced breast cancer, carries a risk of serious pulmonary toxicity, including rare but fatal interstitial lung disease. This study demonstrates that ribociclib directly induces alveolar epithelial cell apoptosis, driving lung injury in mice and human alveolar epithelial cells. Mechanistically, we identify an off-target activation of Mucolipin-1 (MCOLN1) as the critical event, which arrests autophagic flux by blocking autophagosome-lysosome fusion. Moreover, this autophagic impairment precedes and precipitates apoptosis independently of CDK4/6 inhibition. Crucially, we reveal the antidiabetic drug metformin as a potent therapeutic intervention. Metformin rescues ribociclib-induced toxicity both in vitro and in vivo by restoring autophagic flux through suppressing Mucolipin-1 expression to overcome the autophagosome-lysosome fusion blockade. This significantly attenuates epithelial apoptosis, inflammatory infiltration, and pathological damage in the lungs. Our work provides the first demonstration of Mucolipin-1-mediated autophagic arrest as the core mechanism underlying ribociclib's pulmonary toxicity and establishes metformin as a clinically actionable strategy for mitigation, highlighting autophagic flux restoration as a new paradigm for countering kinase inhibitor-related organ toxicities.