LIPE‐AS1 Facilitates Prostate Cancer Progression via Suppressing Cuproptosis Through the miR‐330‐3p/MGAT5 Axis

Cuproptosis, a copper‐dependent form of regulated cell death, represents a potential metabolic vulnerability in cancer. However, the upstream regulators of this process in prostate cancer (PCa) remain unclear. This study identified long noncoding RNA (lncRNA) LIPE‐AS1 as a key suppressor of cuproptosis in PCa. Elevated levels of LIPE‐AS1 were observed in PCa, which inversely correlated with the core cuproptosis gene ferredoxin 1 ( FDX1 ). Silencing LIPE‐AS1 sensitized cells to the cuproptosis inducer elesclomol‐Cu (Ele‐Cu), an effect that was reversible through copper chelation. Mechanistically, cytoplasmic LIPE‐AS1 functioned as a competing endogenous RNA (ceRNA) by sponging miR‐330‐3p, thereby derepressing its target MGAT5 . MGAT5 subsequently modulated the expression of cuproptosis‐associated proteins FDX1, dihydrolipoamide S ‐acetyltransferase (DLAT), and dihydrolipoamide S ‐succinyltransferase (DLST). Rescue experiments demonstrated that MGAT5 overexpression (MGAT5‐OE) reversed the cuproptosis sensitivity induced by LIPE‐AS1 knockdown. In vivo studies revealed that LIPE‐AS1 depletion synergized with elesclomol to suppress tumor growth. Collectively, the LIPE‐AS1/miR‐330‐3p/MGAT5 axis is defined as a critical pathway restraining cuproptosis in PCa, providing a mechanistic basis for targeting this circuit to overcome therapy resistance.