THRSP–MIF Signaling Drives MASH Progression: Hepatology | April 2026

Introduction:

The progression from metabolic dysfunction-associated fatty liver (MAFL) to metabolic dysfunction-associated steatohepatitis (MASH) is driven by complex interactions between hepatocytes and immune cells. This study identifies a novel spatial mechanism in the periportal (PP) zone, where lipogenic hepatocytes communicate with lipid-associated macrophages (LAMs) to promote inflammation and fibrosis.

Why was this study needed?

• The mechanisms driving progression from steatosis to MASH remain incompletely understood.
• Liver zonation may influence disease progression, but its role has been poorly defined.
• Lipid-associated macrophages (LAMs) are increasingly recognized as key mediators of fibrosis.
• Novel molecular targets beyond current therapies are urgently needed.
• Understanding cell-to-cell communication may enable precision therapies for MASH.

Results:

• THRSP-positive hepatocytes promoted MASH progression by producing palmitic acid and recruiting CD74-positive lipid-associated macrophages through MIF signaling, particularly within the periportal region.
• This hepatocyte–macrophage crosstalk amplified hepatic inflammation, stellate cell activation, and fibrosis, identifying a key mechanism underlying disease progression.
• A novel THRSP inhibitor (C6) significantly reduced inflammation and fibrosis in experimental MASH, highlighting THRSP as a promising therapeutic target.

Clinical Impact:

This study provides important insight into the spatial biology of MASH, demonstrating that fibrosis is driven by localized communication between metabolically active hepatocytes and inflammatory macrophages. Targeting the THRSP–MIF–CD74 signaling axis may offer a new precision approach to prevent fibrosis progression beyond current therapies such as resmetirom.

Bottom Line:

Periportal THRSP-positive hepatocytes orchestrate MASH progression by recruiting CD74-positive lipid-associated macrophages through MIF signaling. Interrupting this pathway with THRSP inhibition represents a promising new strategy for treating MASH-associated liver fibrosis.