HSD17B13 Deficiency Modulates Interferon Signaling to Ameliorate Metabolic Dysfunction-Associated Steatohepatitis Fibrosis

Hsd17b13 depletion was sufficient to induce hepatocyte interferon signaling, and induction of this pathway was sufficient to inhibit medium-exposed HSCs. We show that DiHOMEs, lipokines derived from linoleic acid, are likely the mediator by which HSD17B13 affects interferon signaling. Finally, we find a similar upregulation of hepatic interferon signaling in human subjects who carry the HSD17B13 rs72613567 loss-of-function variant.

Collectively, our data suggest that loss of HSD17B13 attenuates MASH fibrosis through augmentation of protective hepatocyte interferon signaling to mitigate HSC activation. These findings shed new light on potential strategies to treat MASH-associated fibrosis.