OSBPL3 Drives Colorectal Cancer Growth by Rewiring Cholesterol and Fat Metabolism

Researchers report that a lipid-binding protein called OSBPL3 acts as a driver of colorectal cancer, promoting tumor growth by reshaping how cancer cells produce and use cholesterol and fatty acids. The work, published in the Journal of Translational Medicine, describes a regulatory loop in which OSBPL3 boosts production of a cholesterol byproduct, 25-hydroxycholesterol, which in turn suppresses a microRNA that normally restrains OSBPL3 itself.

Colorectal cancer remains one of the most common and deadly malignancies, and factors such as overweight and obesity are thought to raise risk partly by disturbing lipid metabolism. OSBPL3, a member of the oxysterol-binding protein-like family, was found to be significantly upregulated in colorectal cancer tissues, and higher levels of the protein were associated with poorer patient prognosis.

To probe the protein’s function, the team combined RNA sequencing with Western blot analysis to examine links between OSBPL3 and lipid metabolic reprogramming. They measured triglyceride and total cholesterol levels using biochemical assay kits, and quantified 25-hydroxycholesterol with liquid chromatography-tandem mass spectrometry. Functional assays tested whether the protein affected the proliferation, migration and invasion of colorectal cancer cells.

The results showed that OSBPL3 promoted all three malignant behaviors in vitro, and also drove epithelial-mesenchymal transition, a cellular program that allows cancer cells to become more motile and invasive. Mechanistically, cells with elevated OSBPL3 showed increased cholesterol biosynthesis and greater production of 25-hydroxycholesterol, the oxysterol at the center of the newly described signaling axis.

That byproduct proved to be a key messenger. According to the study, 25-hydroxycholesterol inhibited the expression of miR-7-5p, a microRNA that directly targets OSBPL3 and negatively regulates it. This creates a feedback loop: more OSBPL3 leads to more 25-hydroxycholesterol, which suppresses the microRNA that would otherwise keep OSBPL3 in check, allowing the cycle to reinforce itself.

The researchers also traced a second arm of the pathway. OSBPL3 suppressed the phosphorylation of AMP-activated protein kinase, or AMPK, a cellular energy sensor. With AMPK signaling dampened, the transcription factor SREBP1 became activated, which the authors found enhanced fatty acid synthesis. They tested SREBP1’s role directly by silencing the gene in colorectal cancer cells with altered OSBPL3 expression.

The interaction between miR-7-5p and OSBPL3 was validated with a dual-luciferase reporter assay, a standard technique for confirming that one molecule binds the regulatory region of another. The team then moved into animal work, assessing effects in nude mouse xenograft models and in C57BL/6 mice. In vivo, OSBPL3 overexpression promoted tumor growth in the nude mice, and administration of 25-hydroxycholesterol promoted tumor growth in the C57BL/6 model.

Taken together, the authors argue that the findings support a role for the 25-HC/miR-7-5p/OSBPL3/SREBP1 axis in lipid metabolic reprogramming and colorectal cancer progression. The study’s conclusions are stated cautiously: the data implicate 25-hydroxycholesterol, miR-7-5p and OSBPL3 in a potentially coordinated regulatory network, and the authors note that the clinical translational value of these findings remains to be established.

Several caveats apply. The article was published as an accepted manuscript shared ahead of the final version of record, a version the publisher notes is subject to further edits. The mechanistic work relies on cell lines and mouse models, which capture specific experimental conditions rather than the full complexity of human tumors, and the reported associations between OSBPL3 and prognosis in patient tissues will require independent validation before any clinical application can be considered.

Subject of Research: The role of OSBPL3 in lipid metabolic reprogramming and colorectal cancer progression

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

Article References: Zhou, X., Han, Y., Sun, L., Wang, N., Bi, Y., Geng, Y., Zhu, X., Liu, S., Chen, N., Piao, Y., Ren, X., & Han, L. (2026). OSBPL3 regulates lipid metabolism and promotes colorectal cancer progression via the 25-HC-mediated miR−7−5p/OSBPL3/SREBP1 signaling loop. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09102-0

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09102-0

Keywords: colorectal cancer, OSBPL3, lipid metabolism, 25-hydroxycholesterol, miR-7-5p, SREBP1, cholesterol biosynthesis, AMPK, EMT, xenograft models, Journal of Translational Medicine, regulates