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. Graphical LIPE-AS1 is markedly upregulated and serves as a competitive endogenous RNA that sponges miR-330-3p. This sequestration relieves miR-330-3p-mediated repression of MGAT5, leading to elevated MGAT5, which subsequently suppresses cuproptosis-related proteins FDX1, DLAT, and DLST, thus diminishing cuproptosis sensitivity. Importantly, disrupting this axis with Elesclomol enhances cuproptosis and suggests a potential therapeutic strategy for this malignancy.
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