Mevalonate pathway regulates double-negative regulatory T cell stability in metabolic dysfunction–associated steatotic liver disease

Lipid metabolism dysfunction and immune imbalance are critical pathogenic drivers of metabolic dysfunction–associated steatotic liver disease (MASLD). Double-negative regulatory T cells (DNTreg) are important immune regulatory cells that maintain liver immune homeostasis. However, their survival and function are compromised in MASLD. Herein, we found that mevalonate pathway and its rate-limiting enzyme HMG-CoA reductase (HMGCR) were significantly down-regulated in DNTreg from both mice and patients with MASLD, correlating with impaired DNTreg viability and immunosuppressive function. Arachidonic acid is enriched in MASLD liver and inhibits DNTreg HMGCR expression. Geranylgeranyl pyrophosphate (GGPP), a downstream product of HMGCR, mediates RAC1 geranylgeranylation, which facilitates its interaction with mitochondrial CLPX protease, thereby enhancing mitochondrial function and immunoregulatory activity of DNTreg. Adoptive transfer of Pggt1b +/− DNTreg into MASLD mice demonstrated significantly diminished therapeutic efficacy compared with wild-type DNTreg. In conclusion, mevalonate metabolism–mediated geranylgeranylation is essential for the suppressive activity and immune homeostasis of DNTreg in MASLD.