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

Mar 31, 2026Communications biology

Lisinopril may restore cell cleaning and change fat use by activating BI1 in ALS

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Abstract

Lisinopril was identified as a BI1 activator that regulates lipid metabolism in ALS mice.

BI1 is downregulated in ALS and is linked to disrupted lipid metabolism.
Lisinopril treatment increased BI1 protein expression and stabilized mitochondrial function.
The drug also regulated autophagy pathways and maintained neuromuscular junction integrity.
Changes in lipid metabolism included shifts toward glucose oxidation and alterations in triglycerides, sphingolipids, and glycerophospholipids.
Lisinopril inhibited the TGF-β1/Smad2/3 pathway, resulting in reduced muscle fibrosis and collagen deposition.

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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 SOD1-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. G93A

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

Abstract

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