Mevalonate Pathway Disruption Impairs Liver Immune Regulation in MASLD in Mice and Human Cells

Disruption of the mevalonate pathway directly impairs the viability and immunosuppressive function of double-negative regulatory T cells (DNTreg) in metabolic dysfunction–associated steatotic liver disease (MASLD), according to a study published in Science Advances science.orgScience Advancesscience.orgOpen source ↗.

Researchers identified that the mevalonate pathway and its rate-limiting enzyme, HMG-CoA reductase (HMGCR), are significantly downregulated in DNTreg isolated from both MASLD mouse models and human patients. This suppression correlates with diminished viability and compromised immunoregulatory activity of these cells, which normally maintain immune homeostasis in liver tissue. The authors reported that arachidonic acid accumulates in the steatotic liver and acts as a direct inhibitor of HMGCR expression in DNTreg.

Mechanistically, geranylgeranyl pyrophosphate (GGPP), a downstream product of HMGCR metabolism, promotes the geranylgeranylation of RAC1. This lipid modification facilitates the interaction of RAC1 with the mitochondrial protease CLPX, which supports mitochondrial function and sustains the suppressive capacity of DNTreg. In cell transfer experiments, adoptive transfer of Pggt1b+/− DNTreg into MASLD mice exhibited significantly reduced therapeutic efficacy compared to wild-type DNTreg.