Lisinopril activates BI1 to reprogram lipid metabolism and restore autophagy in ALS

  • Commun Biol. 2026 Mar 31;9(1):705. doi: 10.1038/s42003-026-09930-2.
Hanlan Yin  1 ,  Zhichao Ren  1 ,  Yan Zhang  1 ,  Yuxiang Wang  1 ,  Yiyang Sun  1 ,  Xueqi Fu  1 ,  Wenfu Yan  2 ,  Fuqiang Zhang  #  3 ,  Linlin Zeng  #  4
Affiliations
  • 1. Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Science, Jilin University, Changchun, China.
  • 2. State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, College of Chemistry, Jilin University, Changchun, China.
  • 3. Scientific Research Centre of China-Japan Union Hospital, Jilin University, Changchun, China. [email protected].
  • 4. Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Science, Jilin University, Changchun, China. [email protected].
  • # Contributed equally.
PMID: 41917198 DOI: 10.1038/s42003-026-09930-2
Abstract

Amyotrophic lateral sclerosis (ALS) involves disrupted lipid metabolism. Bax Inhibitor 1 (BI1), an endoplasmic reticulum protein downregulated in ALS neuroprotective, represents a therapeutic target, but its metabolic regulatory mechanisms are incompletely understood. Using transcriptomics in skeletal muscle of ALS mice pre- and post-BI1 treatment, we identified BI1-regulated pathways. Structure-based virtual screening of FDA-approved compounds nominated lisinopril as a BI1 activator. Lisinopril upregulated BI1 protein expression, stabilizing mitochondrial membrane potential and protecting against SOD1G93A-induced Apoptosis in NSC34 cells. Concurrently, it regulated TGF-β1/mTOR-dependent Autophagy, maintained NMJ integrity, and reshaped triglyceride/sphingolipid/glycerophospholipid metabolism to attenuate spinal cord pathology in ALS mice, promoting energy metabolism shift toward glucose oxidation. Additionally, lisinopril inhibited the TGF-β1/SMAD2/3 pathway to alleviate muscle fibrosis, downregulate ACP5/FN expression, and reduce type I Collagen deposition. In conclusion, this study provides evidence that pharmacological activation of BI1 by lisinopril suppresses TGF-β1, modulates lipid metabolism, and ameliorates ALS pathology, demonstrating promising therapeutic repurposing potential.

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