RIPK1 senses S-adenosylmethionine scarcity to drive cell death and inflammation

The capacity of cells to sense and respond to nutrient availability is essential for metabolic homeostasis. Failure in this process may cause cell death and associated diseases. While nutrient sensing in metabolic pathways is well understood, the mechanisms linking nutrient signals to cell death remain unclear. Here, we show that RIPK1, a key mediator of cell death and inflammation, senses methionine and its metabolite, S -adenosylmethionine (SAM), to dictate cell survival and death. SAM-mediated symmetrical dimethylation at RIPK1 Arg606 by PRMT5 functions as a physiological protective brake against RIPK1 activation. Metabolic perturbations, such as methionine restriction or disrupted one-carbon flux, reduce SAM levels and unmask Arg606, promoting RIPK1 self-association and trans -activation, thereby triggering apoptosis and inflammation. Thus, RIPK1 is a physiological SAM sensor linking methionine and one-carbon metabolism to the control of life-or-death decisions. Our findings suggest that RIPK1 could be a potential target for diseases associated with disrupted SAM availability. • Depletion of methionine or SAM activates RIPK1, inducing apoptosis and inflammation • RIPK1 senses methionine and SAM levels through symmetric dimethylation at Arg606 • R606 residue is essential for RIPK1 self-association and activation upon TNF sensing • PRMT5 mediates RIPK1 dimethylation to prevent liver cell death and inflammation How cells sense nutrients to maintain homeostasis and prevent cell death is a fundamental question. Chen et al. reveal that cells use RIPK1 to sense levels of the nutrient methionine and its metabolite S -adenosylmethionine (SAM). When SAM levels drop due to metabolic changes, RIPK1 triggers apoptosis and inflammation.