UPF1, modified by METTL1 via m⁷G, enhances carboplatin sensitivity in retinoblastoma by degrading SIRT1 mRNA and inhibiting mitophagy

Chemotherapy resistance remains a major therapeutic challenge in retinoblastoma (RB). While the RNA-binding protein UPF1 is known to influence tumor progression by regulating both coding and non-coding RNAs, its specific function and molecular mechanisms in RB are still unclear. Carboplatin (CBP)-resistant cell lines were derived from WERI‑RB‑1 and Y79 cells via stepwise dose escalation. Resistance was assessed using colony formation and apoptosis assays. Overall mRNA m7G levels in tissues and cells were measured by RNA dot blot. To investigate METTL1‑mediated regulation of UPF1, m⁷G‑MeRIP and RIP assays were performed. The UPF1-SIRT1 interaction was examined by RIP. Mitophagy was evaluated via immunofluorescence co‑localization of LC3B or Parkin with mitochondria. The role of UPF1 was validated in a tumor xenograft model, followed by TUNEL staining and immunohistochemistry. CBP‑resistant RB cells exhibited decreased UPF1 levels compared with parental cells, and restoring UPF1 expression resensitized resistant cells to CBP. Mechanistically, METTL1 binds to UPF1 mRNA and promoted its m⁷G modification, thereby enhancing UPF1 mRNA stability. UPF1 facilitated the degradation of SIRT1 mRNA and suppressed SIRT1 protein expression, leading to inhibition of mitophagy and ultimately increasing CBP sensitivity. Moreover, UPF1 upregulation suppressed tumor growth and improved CBP response in mouse xenograft models. UPF1, whose expression is stabilized by METTL1-mediated m⁷G modification, enhances carboplatin sensitivity in retinoblastoma cells through suppressing mitophagy via SIRT1 mRNA degradation.