ArticleCell & bioscience2026
Macrophage PSRC1 attenuates atherosclerosis via extracellular vesicle-mediated MBD2 delivery to induce PCSK9 promoter methylation in hepatocytes.
Article in Cell & bioscience, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundAtherosclerotic cardiovascular disease (ASCVD) is driven by dysregulated lipid metabolism and chronic inflammation. However, the mechanisms governing immune-liver crosstalk in this context remain poorly defined. Proline/serine-rich coiled-coil protein 1 (PSRC1) is a known regulator of cholesterol metabolism, but whether macrophage-derived PSRC1 influences hepatic functions via intercellular communication is unknown.
methodsThe relationship between macrophage PSRC1 and hepatic PCSK9 was examined in patients with coronary artery disease and murine models. We employed AAV6-mediated macrophage-specific targeting and whole-body Psrc1⁻/⁻ mice to evaluate cell-type-specific effects. Macrophage-hepatocyte communication was investigated using transwell systems and genetic blockade of EV secretion (sh-Rab27a). The selectivity of EV cargo loading was validated by protease protection assays and TSG101 interaction analysis. In vivo EV tracking (DiI-labeling) and ChIP-qPCR for DNMT recruitment were performed to elucidate the systemic and epigenetic mechanisms.
resultsMacrophage PSRC1 expression was significantly reduced in atherosclerotic conditions and inversely correlated with hepatic PCSK9 levels. Macrophage-specific PSRC1 depletion alone was sufficient to recapitulate the systemic hypercholesterolemia and accelerated atherosclerosis observed in whole-body knockout models. PSRC1 was found to interact with TSG101 to promote the selective loading of MBD2 into the EV lumen, a process confirmed by protease protection. These MBD2-enriched EVs were preferentially sequestered by the liver after systemic administration. Mechanistically, transferred MBD2 functioned as an epigenetic scaffold, recruiting DNA methyltransferases (DNMT1/3A) to the PCSK9 promoter to drive CpG hypermethylation and transcriptional repression. In vivo, administration of MBD2-enriched EVs significantly reduced hepatic PCSK9 protein, lowered plasma cholesterol, and enhanced plaque stability in ApoE⁻/⁻ mice.
conclusionsOur findings uncover a novel macrophage-liver epigenetic axis where macrophage PSRC1 controls systemic cholesterol homeostasis by regulating the EV-mediated delivery of MBD2. This "Reader-recruits-Writer" mechanism provides a refined understanding of immune-metabolic crosstalk and suggests that engineered EV-based MBD2 delivery represents a promising therapeutic strategy for ASCVD.
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