CARM1 drives sepsis-induced lung injury by coupling PKM2-governed metabolic rewiring to macrophage ferroptosis.

Ferroptosis has been linked to impaired macrophage function and acute lung injury (ALI), a condition associated with high mortality. Nevertheless, the regulatory mechanisms underlying ferroptosis remain to be fully elucidated. In pro-inflammatory macrophages, glycolysis is preferentially upregulated, with pyruvate kinase M2 (PKM2) acting as a key regulatory enzyme. Here, we elucidate a distinct functional role of ferroptosis in this context. We identified CARM1, an arginine methyltransferase, as a crucial metabolic mediator that promotes ferroptosis by activating PKM2-dependent glycolysis. CARM1 is ubiquitously expressed and hyperactivated in sepsis models, leading to elevated levels of glycolysis-related enzymes, including LDHA and PKM2. Therapeutic intervention with the CARM1 inhibitor TP-064 significantly attenuated inflammatory responses in macrophages and ameliorated ALI in septic models. Furthermore, TP-064 suppressed ferroptosis and PKM2-dependent glycolysis both in vitro and in vivo. Notably, genetic ablation of CARM1 phenocopied the inhibitory effects of TP-064. Pharmacological inhibition of PKM2 by shikonin also effectively suppressed ferroptosis-associated markers and alleviated ALI. Taken together, these findings establish CARM1 as an integrative node that couples metabolic reprogramming with PKM2 activity to regulate ferroptosis. Therefore, pharmacological targeting CARM1 may represent a promising therapeutic strategy for mitigating dysregulated ferroptosis and cytokine storm syndromes driven by hyper-glycolytic states.