INPP5A promotes breast cancer progression through lipid metabolism reprogramming

Abstract Lipid metabolism reprogramming is a crucial feature of cancer progression, influencing tumor growth and patient prognosis. This study aimed to identify lipid metabolism-related risk genes and establish a prognostic model for breast cancer, and to systematically investigate the functional role of INPP5A in disease progression. We identified six independent risk genes, including INPP5A, from metabolism-related gene sets using a multi-step regression and machine learning strategy. On this basis, we developed and validated a prognostic risk prediction model. By integrating transcriptomic, lipidomic, metabolomic and functional analyses, we examined the effects of INPP5A on breast cancer cell proliferation, migration, and invasion, with particular emphasis on oxidative phosphorylation (OXPHOS) and lipid metabolism. We further explored the relationship between INPP5A and its candidate downstream effector ECH1. The risk score effectively stratified breast cancer patients by prognosis, with INPP5A showing the highest risk ratio. INPP5A was upregulated in breast cancer tissues and correlated with poor survival. Functional experiments showed that INPP5A promotes proliferation, migration and invasion, accompanied by altered lipid homeostasis, lipid droplet accumulation and OXPHOS activity. INPP5A knockdown reduced ECH1 expression, while ECH1 restoration partially rescued the metabolic and phenotypic changes caused by INPP5A loss. Conversely, altering ECH1 levels did not consistently affect INPP5A expression, suggesting that INPP5A acts upstream of ECH1 in a unidirectional manner. Our findings identify INPP5A as a potential therapeutic target in breast cancer and suggest that it promotes tumor progression by sustaining ECH1 expression and OXPHOS activity. This work provides new experimental evidence for understanding the metabolic mechanisms underlying breast cancer pathogenesis.