DTC1225, a novel benzothiazole-based compound, ameliorates MASLD by restoring metabolic-redox homeostasis and promoting hepatic lipid remodeling.
Abstract
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a highly prevalent chronic liver disorder for which effective pharmacotherapies remain limited. Autophagy is a fundamental intracellular degradation and recycling process that maintains hepatic homeostasis by regulating lipid metabolism and mitigating lipid-induced cellular stress, highlighting its potential as a therapeutic target for MASLD. APPROACH AND RESULTS: Through an in vitro reporter-based screening of a chemical compound library, DTC1225, a novel benzothiazole-derived compound was identified as an autophagy activator that inhibited mTORC1 signaling, promoted transcription factor EB nuclear translocation, activated the autophagy-lysosome pathway, and enhanced autophagic flux. Functionally, DTC1225 reduced lipid droplet accumulation in steatotic HepG2 cells and differentiated 3 T3-L1 adipocytes, accompanied by alterations in autophagy-related markers and gene expression, and attenuation of MASLD-associated cellular injury. In a 4-month fructose, palmitate, and cholesterol diet-induced mouse model of MASLD, DTC1225 alleviated hepatic injury, modulated autophagic machinery, improved lipid metabolic profiles, restored redox homeostasis, and attenuated early-stage hepatic fibrosis. Hepatic lipidomics analysis further revealed that DTC1225 induced selective structural lipid remodeling, shifting the lipidome toward longer-chain and more unsaturated species, with a preferential enrichment of n-3 polyunsaturated fatty acids-containing lipids, which may contribute to attenuated lipotoxicity and modulation of membrane fluidity. CONCLUSIONS: DTC1225 ameliorates MASLD-associated hepatic pathology through multifaceted mechanisms involving coordinated modulation of autophagy-related pathways, lipid metabolism, and redox homeostasis, accompanied by favorable hepatic lipid remodeling. These findings provide a critical rationale for further development of DTC1225 as an innovative therapeutic candidate for MASLD and its associated complications.
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