Lithium carbonate induces myofibroblast necroptosis to reverse pulmonary fibrosis

Pulmonary fibrosis (PF) is a fatal disease with limited therapeutic options. Myofibroblasts, central to the pathogenesis of PF, are the primary collagen-producing cells that drive fibrosis. However, therapeutic targeting of myofibroblasts faces formidable challenges owing to their autonomous activation, persistent proliferation, and resistance to apoptosis. Here, we show that lithium carbonate (LC), a clinically approved mood stabilizer, effectively depletes myofibroblasts during fibrosis progression. Mechanistically, LC promotes alveolar macrophages (AMs) to produce TNF-α, which activates pro-caspase-8 signaling without inducing myofibroblast apoptosis. LC directly binds to and inactivates pro-caspase-8, inducing to RIP1/RIP3/MLKL-dependent necroptosis of myofibroblasts. These mechanistic insights have enabled the repurposing of LC as a therapeutic strategy to reverse established lung fibrosis in mouse models. Our findings provide a myofibroblast-targeting strategy and highlight its potential in PF treatment.