# Hyodeoxycholic acid attenuates atherosclerosis by antagonizing FXR and modulating the PD-1/mTORC1 signaling axis

## TL;DR

Hyodeoxycholic acid (HDCA) helps reduce atherosclerosis by changing how regulatory T cells function and move, offering a new way to treat this disease.

## Contribution

HDCA is shown to antagonize FXR and modulate the PD-1/mTORC1 axis in Tregs, revealing a novel immunometabolic target for atherosclerosis.

## Key findings

- HDCA therapy reduced plaque burden in atherosclerosis models by enhancing Treg migration and function.
- HDCA antagonizes FXR, shifting Treg metabolism from fatty acid oxidation to glycolysis.
- HDCA reduces PD-1 signaling and suppresses ZNF671, improving Treg migration and immune regulation.

## Abstract

Accumulating evidence suggested that bile acids play a significant role in modulating metabolic and inflammatory diseases. In this study, we investigated the roles of the farnesoid X receptor (FXR) and its endogenous antagonist hyodeoxycholic acid (HDCA) in the development of atherosclerosis (AS). We found that serum HDCA was significantly reduced in patients with AS, and systemic HDCA therapy attenuated plaque burden in vivo. Adoptive transfer of HDCA-treated Foxp3+ Tregs into ApoE-deficient recipients reduced lesion growth, whereas FXR-deficient Tregs failed to confer benefit. HDCA enhanced Treg migration and accumulation within plaques and reprogrammed Treg metabolism by antagonizing FXR and modulating PD-1/mTORC1 signaling. This shift relieved CPT1a-driven fatty acid oxidation bias, increased glycolysis and ATP production, and improved migratory capacity and effector function. We further identify ZNF671 as a transcriptional inhibitor of Treg migration that is mitigated by HDCA-dependent metabolic switching. Collectively, HDCA reduced FXR-mediated metabolic constraints while activating glycolytic and migratory programs in Tregs, thereby improving lipid handling and immune regulation within the plaque microenvironment. These findings position the HDCA–FXR–PD-1/mTORC1 axis as a novel immunometabolic target for AS.

HDCA-driven FXR antagonism reprograms Treg metabolism and migration to inhibit atherosclerotic plaque growth. The schematic summarizes how the bile acid hyodeoxycholic acid (HDCA) protects against atherosclerosis (AS) by acting directly on regulatory T cells (Tregs). Upper panel (in vivo overview, ApoE−/− AS blood vessel): HDCA promotes recruitment and infiltration of donor Foxp3+ Tregs into atherosclerotic plaques and reduces lipid deposition (fatty acids and cholesterol) within lesions. The protective effect depends on Treg-intrinsic FXR signaling being present and antagonized: HDCA-treated donor Tregs attenuate plaque development, whereas FXR-deficient Tregs do not confer benefit. HDCA also diminishes PD-1 signaling, which enhances Treg immune function and supports migration into the plaque microenvironment. Lower panel (inside Tregs, mechanistic view): HDCA antagonizes the Treg FXR receptor. This inhibition 1) downregulates the transcriptional repressor ZNF671, relieving its constraint on migratory gene programs; and 2) attenuates PD-1 signaling and its downstream suppression of mTORC1. The concerted blockade of these pathways initiates a metabolic switch: it suppresses FXR/CPT1a-driven fatty acid oxidation (FAO) and activates mTORC1, leading to enhanced glycolysis and ATP production. This metabolic reprogramming is further characterized by a global remodeling of the Treg metabolome, including altered amino acid flux and a shift toward unsaturated fatty acids. The resulting bioenergetic and biosynthetic surge fuels cytoskeletal reorganization, increases STAT5 phosphorylation, and enhances both the migratory capacity and suppressive functions of Tregs. Together, HDCA-driven FXR antagonism coordinates transcriptional, metabolic, and signaling changes that enhance Treg motility and function, leading to improved lipid handling and plaque stabilization.Image 1

•HDCA antagonizes FXR to reprogram Treg bioenergetics in atherosclerosis.•HDCA shifts Tregs from FAO/OXPHOS to mTORC1-driven glycolysis.•FXR antagonism lowers CPT1a, remodels mitochondria and lipid droplets.•HDCA reduces PD-1/SHP-2 signaling, enhancing Treg migration into plaques.•ZNF671 suppression and STAT5 activation further boost Treg function.

HDCA antagonizes FXR to reprogram Treg bioenergetics in atherosclerosis.

HDCA shifts Tregs from FAO/OXPHOS to mTORC1-driven glycolysis.

FXR antagonism lowers CPT1a, remodels mitochondria and lipid droplets.

HDCA reduces PD-1/SHP-2 signaling, enhancing Treg migration into plaques.

ZNF671 suppression and STAT5 activation further boost Treg function.