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

Mevalonate pathway activity is significantly reduced in DNTreg from both mice and patients with MASLD, with lower HMGCR linked to reduced DNTreg viability and immunosuppressive function.

• Why it matters: Lipid-driven immune imbalance is a key driver of MASLD, yet DNTreg survival and suppressive activity are compromised; the pathway controlling this defect was unclear.
• What they did: The study measured mevalonate pathway and HMGCR expression in DNTreg from MASLD mice and patients, tested how arachidonic acid affects HMGCR, and used GGPP to support RAC1 geranylgeranylation and mitochondrial CLPX interaction.
• The result: In MASLD mice, adoptive transfer of Pggt1b +/- DNTreg showed significantly diminished therapeutic efficacy versus wild-type DNTreg, implying mevalonate-mediated geranylgeranylation is required for DNTreg immune homeostasis.

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