GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE301nnn/GSE301454/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE301454GEOGSEfalseLisinopril Activates BI1 to Reprogram Lipid Metabolism and Restore Autophagy in ALSBackground Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. Abnormal lipid metabolism represents a critical pathogenic determinant and key therapeutic target in ALS. Bax inhibitor 1 (BI1), an endoplasmic reticulum membrane protein, is downregulated in ALS and exhibits neuroprotective properties. However, due to incomplete understanding of its metabolic regulatory mechanisms, targeting BI1 for ALS therapy remains an area requiring further investigation. Methods Skeletal muscles from ALS mice pre- and post-BI1 treatment underwent transcriptomic analysis to identify BI1-regulated target genes and signaling pathways. Subsequently, we performed a structure-based virtual screening of FDA-approved compounds to identify potential BI1 activators. Lisinopril was selected as a lead candidate, and its effects were validated in SOD1G93A-transfected NSC34 cells and an ALS mouse model. Mechanistic studies explored its impact on autophagy regulation, lipid metabolism, and TGF-β1signaling pathways. Results Lisinopril upregulated BI1 protein expression, stabilizing mitochondrial membrane potential and conferring resistance to SOD1G93A-induced apoptosis. Concurrently, it regulated TGF-β1/PI3K/AKT/mTOR-dependent autophagy, maintained neuromuscular junction (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. Conclusions Our study elucidated the molecular mechanism by which BI1 remodels lipid metabolism via the TGF-β1 pathway to influence ALS pathogenesis. These findings provided the first evidence that pharmacological activation of BI1 suppresses TGF-β1 expression and modulates triglyceride/sphingolipid/glycerophospholipid metabolism, thereby ameliorating ALS-related pathological phenotypes. Notably, repurposing lisinopril (an FDA-approved drug for hypertension) held promise for ALS therapy.2026/02/27GSE301454GSM9083444GSM9083443GSM9083446GSM9083445GSM9083448GSM9083447GSM9083449GSM9083451GSM9083450GSM9083442GSM9083452GSM908344124247301454Mus musculus