Lactate is a central metabolite generated during glycolysis. In recent years, it has emerged as an important metabolic signaling molecule, with its biological functions studied primarily in the context of cancer. However, how lactate translates metabolic state into cell-fate decisions—particularly how it directly regulates necroptosis under physiological and non-cancer pathological conditions—remains largely unknown.

In a recent study published in Cell Metabolism, a research team led by Prof. SUN Liming from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences, in collaboration with Prof. SUN Yingxian from the First Hospital of China Medical University, revealed a previously unrecognized mechanism through which the metabolic signal lactate directly couples cellular metabolic state to the necroptotic signaling pathway through RIPK3 lactylation.

The study further showed that this metabolic cell-death axis plays dual roles in pathological tissue injury and physiological tissue remodeling, offering a new conceptual framework for understanding how metabolic signals govern cell-fate decisions.

In this study, the researchers first screened a small-molecule library and identified lactate as a key regulator of necroptosis. Mechanistically, lactate promotes lactylation of RIPK3 at lysine 63 (K63), thereby directly linking cellular metabolic state to the necroptotic signaling pathway.

The acetyltransferase PCAF catalyzes RIPK3-K63 lactylation, enhancing RIPK3 kinase activity and promoting its interaction with the downstream executioner MLKL, ultimately triggering necroptosis. In contrast, substitution of K63 with the non-lactylatable mutant (RIPK3-K63R) markedly reduced RIPK3 kinase activity and significantly suppressed necroptosis, indicating that RIPK3-K63 lactylation acts as a critical molecular switch controlling necroptotic signaling.

To investigate whether inhibition of RIPK3-K63 lactylation could protect tissues from pathological injury, the researchers used mouse models of myocardial ischemia-reperfusion injury and influenza virus infection.

RIPK3-K63R knock-in mice showed significantly reduced myocardial infarct size following ischemia-reperfusion injury. Pharmacological inhibition of PCAF also attenuated cardiac injury by suppressing RIPK3 lactylation.

In the influenza infection model, RIPK3-K63R mutant mice showed markedly reduced lung pathology, slower body-weight loss, and significantly improved survival. Together, these findings indicate that RIPK3-K63-lactylation-driven necroptosis is a major driver of tissue injury in ischemic and viral diseases, highlighting this modification as a promising therapeutic target for organ protection.

Notably, the same metabolic cell-death mechanism serves a completely different physiological function. During high-intensity exercise, the large amount of lactate generated in skeletal muscle induces RIPK3-K63 lactylation and moderately activates necroptosis in myofibers.

This controlled necroptotic response stimulates the activation and proliferation of muscle stem cells (MuSCs), thereby promoting post-exercise skeletal muscle regeneration and remodeling.

Overall, the study identifies lactate as a metabolic signaling molecule that directly regulates necroptosis through RIPK3 lactylation, revealing a previously unrecognized "metabolite–post-translational modification–necroptosis" regulatory paradigm.

By showing that this metabolic cell-death axis drives tissue injury under pathological conditions while promoting tissue remodeling under physiological conditions, the study provides a new conceptual framework for understanding how metabolic state governs cell-fate decisions.

According to the researchers, these findings not only deepen our understanding of how metabolism regulates regulated cell death but also offer new opportunities for therapeutic intervention in ischemia-reperfusion injury, viral infectious diseases, and regenerative medicine.