A gut-liver lipid flux checkpoint mediates FAHFA protection from MASLD.

Pharmacotherapies for metabolic dysfunction-associated steatotic liver disease (MASLD) remain limited. Although resmetirom and semaglutide have approvals for MASH, gut-liver axis options are still needed. Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) offer anti-inflammatory and metabolic benefits but are constrained by poor stability and synthesis complexity. We develop a modular, scalable chemistry platform that installs bioisosteric linkages to generate orally stable, gut-retentive FAHFAs. High-throughput screening identifies lead candidates (12-TAASA, 12-HDTZSA) that selectively inhibit intestinal lipid handling while sparing glucose absorption. In a diet-induced MASLD model, oral dosing reduces weight gain, lowers hepatic triglycerides, improves steatosis histology and liver injury markers, and enhances glycemic control, achieving efficacy comparable to semaglutide. Mechanistically, we identify an intestine-anchored dual-brake mechanism. First, 12-TAASA slows and diminishes gut-to-liver lipid flux in vivo, directly reducing the dietary lipid burden reaching the liver. Second, 12-TAASA and 12-HDTZSA remodel the gut microbiome toward short-chain fatty acid (SCFA)-producing consortia and increase circulating, bacterially derived SCFAs, providing a complementary, microbiota-mediated route to systemic metabolic benefit. Multi-omics integration further implicates a CD44-centered epithelial program, together with allied lipid-handling pathways, as a key intestinal target network governing flux control. These findings position stabilized FAHFAs as gut-localized agents that couple epithelial lipid-uptake restraint with microbiome-derived SCFA signals to reduce gut-to-liver lipid flux, establishing an orally active, dual-action strategy for MASLD.