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

- Published: 2026-11-07 21:26 UTC
- Section: Life & Health › Medicine
- Tags: steatotic liver disease, mevalonate pathway, regulatory T cells, HMGCR enzyme, RAC1 geranylgeranylation
- URL: https://realtech.media/news/rt-132dfcd4a14885e1f07d713c_mevalonate_pathway_disruption/

**Researchers found that suppressed HMGCR activity weakens double-negative regulatory T cells in fatty liver disease in mice and patient samples.**

![Mevalonate Pathway Disruption Impairs Liver Immune Regulation in MASLD in Mice and Human Cells](https://realtech.media/media/2026/11/43c9f144aae1cc08.jpg)
*William C. Shrout, Wikimedia Commons, Public domain*

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 [1].

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 [1]. This suppression correlates with diminished viability and compromised immunoregulatory activity of these cells, which normally maintain immune homeostasis in liver tissue [1]. The authors reported that arachidonic acid accumulates in the steatotic liver and acts as a direct inhibitor of HMGCR expression in DNTreg [1].

Mechanistically, geranylgeranyl pyrophosphate (GGPP), a downstream product of HMGCR metabolism, promotes the geranylgeranylation of RAC1 [1]. This lipid modification facilitates the interaction of RAC1 with the mitochondrial protease CLPX, which supports mitochondrial function and sustains the suppressive capacity of DNTreg [1]. In cell transfer experiments, adoptive transfer of Pggt1b+/− DNTreg into MASLD mice exhibited significantly reduced therapeutic efficacy compared to wild-type DNTreg [1].

## Sources

1. [Science Advances](https://doi.org/10.1126/sciadv.aeb8568)

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Source: RealTech, realtech.media — https://realtech.media/news/rt-132dfcd4a14885e1f07d713c_mevalonate_pathway_disruption/