DN203316, a novel PPARδ agonist, suppresses ferroptotic signaling and fibrogenesis in metabolic dysfunction-associated steatohepatitis

Description

Ye Jin Kim and team traced how dietary cholesterol drives liver scarring in metabolic dysfunction-linked steatohepatitis, and tested a drug that might interrupt it. Their 2026 study combined human liver samples, cholesterol-fed mouse models, and mechanistic work in liver cells and hepatic stellate cells. Ferroptosis, an iron-driven form of cell death, had emerged as a disease driver, but its upstream triggers and link to fibrosis stayed unclear.

Cholesterol-driven disease paired strong lipid damage with loss of the receptor PPAR-delta, breaking redox balance and leaving liver cells open to ferroptosis. DNA released from dying cells then activated STING signaling in stellate cells, switching on profibrotic genes. Both restoring PPAR-delta and treating with DN203316, a new selective PPAR-delta agonist, reversed these effects, and the drug eased ferroptosis, inflammation, and fibrosis without metabolic harm. The authors present DN203316 as a promising strategy against disease progression.

Catalog record

Source: https://europepmc.org/articles/PMC13324369