OSBPL3 regulates lipid metabolism and promotes colorectal cancer progression via the 25-HC-mediated miR−7−5p/OSBPL3/SREBP1 signaling loop

Colorectal cancer (CRC) is associated with high incidence and poor prognosis. Factors such as overweight and obesity may increase the risk of CRC by disrupting lipid metabolism. Oxysterol-binding protein-like 3 (OSBPL3) is upregulated in CRC tissues, but its role in lipid metabolism and disease progression remains unclear. RNA sequencing (RNA-seq) and Western blot analysis were performed to investigate the association between OSBPL3 and lipid metabolic reprogramming. CRC cell proliferation, migration, and invasion were assessed by functional assays. Triglyceride (TG) and total cholesterol (T-CHO) levels were measured using biochemical assay kits, and 25-hydroxycholesterol (25-HC) levels were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to evaluate lipid metabolic alterations. The role of sterol regulatory element-binding protein 1 (SREBP1) was further examined by gene silencing in CRC cells with altered OSBPL3 expression. The interaction between miR-7-5p and OSBPL3 was validated by dual-luciferase reporter assay. In vivo effects were assessed in nude mouse xenograft and C57BL/6 mouse models. OSBPL3 was significantly upregulated in CRC tissues and correlated with poor prognosis. In vitro, OSBPL3 promoted CRC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). Mechanistically, OSBPL3 upregulated cholesterol biosynthesis and increased 25-HC production. 25-HC inhibited miR-7-5p expression, whereas miR-7-5p directly targeted and negatively regulated OSBPL3. Additionally, OSBPL3 suppressed AMP-activated protein kinase (AMPK) phosphorylation, leading to SREBP1 activation and enhanced fatty acid synthesis. In vivo, OSBPL3 overexpression and 25-HC administration promoted tumor growth in nude and C57BL/6 mice, respectively. Collectively, these findings support a role for the 25-HC/ miR−7−5p /OSBPL3/SREBP1 regulatory axis in lipid metabolic reprogramming and CRC progression. In summary, OSBPL3 is associated with altered lipid metabolism and tumor progression in CRC, and our data implicate 25-HC, miR-7-5p , and OSBPL3 in a potentially coordinated regulatory network. These findings provide insights into the metabolic underpinnings of CRC, though their clinical translational value remains to be established.