m ⁶ A ‐Mediated Stabilization of MRPS23 Drives Sihong Le, Yitao Le, Xianshen Sha, Feng Qiu, Ling Zhang

ABSTRACT

Lung cancer remains the leading cause of cancer‐related mortality worldwide, largely due to therapeutic resistance and tumor progression. Mitochondrial ribosomal proteins (MRPs), particularly MRPS23, have recently emerged as critical regulators of cancer progression in various malignancies, while N6‐methyladenosine (m ⁶ A) modification has been established as a key epigenetic mechanism driving tumorigenesis. However, whether MRPS23 is regulated by m ⁶ A modification and contributes to lung cancer pathogenesis remains completely unexplored. Here, we identified MRPS23 as a critical oncogenic driver in non‐small cell lung cancer (NSCLC). MRPS23 expression was significantly upregulated in NSCLC tissues and cell lines, and high MRPS23 levels correlated with poor patient prognosis. Mechanistically, we demonstrated that WTAP ‐mediated m ⁶ A methylation and subsequent IGF2BP3 recognition stabilized MRPS23 mRNA. Functionally, MRPS23 promoted lung cancer progression both in vitro and in vivo. Further mechanistic studies revealed that MRPS23 exerted its oncogenic effects through physical interaction with the molecular chaperone HSPA8, and this interaction was functionally associated with activation of the RAS–RAF–MEK–ERK signaling cascade. However, the precise molecular steps linking the MRPS23‐HSPA8 complex to ERK phosphorylation remain to be fully defined. Collectively, our findings unveil a previously unrecognized m ⁶ A‐dependent MRPS23/HSPA8/ERK regulatory axis in NSCLC progression, highlighting MRPS23 and its associated components as promising prognostic biomarkers and therapeutic targets.