LINC01186-mediated deubiquitination of ACSL4 reprograms lipid metabolism to increase autophagy-mediated angiogenesis in colorectal cancer.

Angiogenesis supports colorectal cancer (CRC) proliferation and metastasis, yet how lipid metabolic reprogramming intersects with angiogenesis signaling remains unclear. Here, we found that LINC01186 is upregulated in CRC and correlates with advanced stage and poor prognosis. Mechanistically, LINC01186 functions as a molecular scaffold that concurrently interacts with the deubiquitinating enzyme USP4 and long-chain fatty acyl-CoA synthetase ACSL4, facilitating USP4-mediated deubiquitination of ACSL4. Elevated ACSL4 facilitates the accumulation of polyunsaturated fatty acids (PUFAs), namely arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid. Notably, elevated PUFA levels protect VEGFA from autophagy-lysosomal degradation by reducing autophagic flux, resulting in VEGFA overexpression and consequent promotion of angiogenesis. The absence of LINC01186 or ACSL4 impairs this signaling cascade, reduces PUFA levels, reactivates the autophagic degradation of VEGFA, and markedly obstructs the migration, invasion, and angiogenesis of CRC cells both in vitro and in vivo. Exogenous PUFA supplementation fully restores these abnormalities, which supports the essential involvement of lipid reprogramming in this mechanism. The LINC01186/ACSL4/VEGFA axis is essential in the formation and progression of CRC, with the overexpression of LINC01186 likely acting as a significant catalyst for excessive angiogenesis and metastatic advancement. Our findings highlight a unique lncRNA-mediated regulatory mechanism that connects deubiquitination, lipid metabolism, autophagy, and angiogenesis. Notably, although ferroptosis was not directly assessed in this study, the LINC01186/USP4/ACSL4 axis may have broader implications for ferroptosis research given that ACSL4 is a critical regulator of ferroptosis. Taken together, these results suggest that the LINC01186/USP4/ACSL4 axis represents a prospective therapeutic target for anti-angiogenic treatment in CRC.