Enhancing Regulatory T cell function by mevalonate pathway inhibition prevents liver fibrosis

Abstract

Liver fibrosis is a well-established risk factor for liver cancer development. Despite extensive mechanistic studies on liver fibrosis, the role of the immune cell network in fibrotic disease remains poorly understood. In this study, we demonstrate that regulatory T cells (Tregs) are involved in preventing liver fibrosis by regulating the mevalonate pathway. Blocking the mevalonate pathway increased the granzyme B secretion from Tregs, while restoring the pathway reduced it. Statin treatment, which inhibits the mevalonate pathway, alleviated liver fibrosis progression and enhanced the immunosuppressive function of Tregs in vivo. Mechanistically, mevalonate products, including geranylgeranyl pyrophosphate, inhibited the phosphorylation and activation of LKB1, that is a key regulator of Treg homeostasis. Furthermore, these products disrupted the interaction between LKB1 and cAMP-dependent protein kinase (PKA), leading to further reduction of LKB1 phosphorylation. These findings suggest that targeting LKB1 in Tregs through statin treatment prevents the progression of liver fibrosis, offering a promising and safe therapeutic strategy for liver disease and liver cancer.