ArticleCell death & disease2025
BRUCE liver-KO enhances MASLD/MASH development in the steatotic PTEN-KO background by impairing mitochondrial metabolism and activating STAT3.
Article in Cell death & disease, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Metabolic dysfunction-associated steatotic liver disease: pathogenic mechanisms and exercise-induced molecular adaptations.Lipids in health and disease · 2026Review
- Exercise and cold exposure as dual physiological stressors in MASLD: AMPK-mediated metabolic adaptation and interorgan crosstalk.Frontiers in physiology · 2026Review
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5 authors.
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Abstract
The IAP BRUCE (Birc6) plays multifaceted roles in apoptosis inhibition, DNA repair, and autophagy. Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), affect up to 30% of the global population, yet their pathogenic mechanisms remain poorly understood. Given BRUCE's high expression in healthy livers and its downregulation in MASLD/MASH, we investigated its functional role using liver-specific BRUCE-KO and BRUCE/PTEN dual liver-KO (DKO) mouse models. PTEN liver-KO provides a steatotic background and reflects a major etiological factor. By 3 months, BRUCE liver-deficiency alone induces MASLD onset, but when combined with PTEN liver-KO, increases DNA damage, apoptosis, oxidative stress, and MASLD-to-MASH progression, characterized by inflammation and fibrosis. Mechanistically, PTEN liver-KO is known to drive hepatosteatosis through AKT-mediated de novo lipogenesis (DNL) (PTEN-KO → AKT → DNL). However, BRUCE liver-KO impairs mitochondrial fatty acid -oxidation (FAO), respiration and ATP generation (BRUCE→Mitochondria→FAO). This distinct yet complementary mechanism of action leads to a 'double hit' of excessive lipid synthesis (PTEN-KO) and impaired lipid clearance (BRUCE-KO), exacerbating steatosis. To elucidate the molecular driver of MASH progression, we found both deficiencies converge on STAT3 activation, a central regulator of inflammation and fibrosis. Further, targeted inhibition of STAT3 with TTI-101 alleviates MASH, establishing a BRUCE/PTEN-STAT3 pathogenic axis. Notably, this axis is conserved in humans, with co-downregulation of BRUCE and PTEN and concurrent STAT3 activation in MASLD/MASH patient specimens. Collectively, these findings establish BRUCE as a key metabolic safeguard against MASLD/MASH, reveal cooperative hepatoprotection by BRUCE/PTEN against MASLD/MASH, and suggest STAT3 inhibition as a targeted therapeutic strategy for BRUCE/PTEN-deficient patients.
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