Disrupted minor intron splicing activates reductive carboxylation-mediated lipogenesis to drive metabolic dysfunction-associated steatotic liver disease progression.

Summary

Minor intron splicing is broadly disrupted during MASH progression, causing Insig1/2 intron retention, SREBP1c activation, and a switch to IDH1-driven reductive carboxylation that fuels de novo lipogenesis and ammonia accumulation to initiate fibrosis. Ammonia clearance or IDH1 inhibition blocked fibrogenesis, and Zrsr1 overexpression rescued splicing defects and disease. These define a splicing-metabolism checkpoint as a therapeutic target in MASLD/MASH.

Key Findings

• Minor intron splicing is disrupted in mouse and human MASH, with Insig1/Insig2 intron retention driving proteolytic activation of SREBP1c.
• Disruption triggers IDH1-mediated reductive carboxylation and de novo lipogenesis with hepatic ammonia accumulation that initiates fibrosis.
• Ammonia clearance or IDH1 inhibition blocked hepatic fibrogenesis and mitigated MASH progression.
• Zrsr1 overexpression restored splicing and ameliorated MASH, highlighting minor intron splicing dysfunction as a pathogenic mechanism and therapeutic target.

Clinical Implications

Suggests testing IDH1 inhibitors, ammonia-lowering strategies, or splicing modulators in MASH; provides candidate biomarkers (minor intron retention signatures) to stratify patients and monitor response.

Limitations

• Primarily preclinical; human interventional validation is pending.
• Specificity and safety of targeting minor intron splicing or IDH1 in humans remain to be established.

Future Directions

Validate intron retention signatures and ammonia/IDH1 axes as biomarkers/targets in prospective human cohorts; test combinatorial therapies (IDH1 inhibition plus ammonia-lowering) and define patient subsets most likely to benefit.