SHP1-Mediated FTO Dephosphorylation Regulates Mitophagy and Promotes Tumor Progression via N(6)-Methyladenosine in Colorectal Cancer.

Abstract

Colorectal cancer (CRC) progression and resistance to therapy are driven by complex molecular mechanisms, implying the importance of identifying biomarkers and developing treatment strategies. Whereas Src homology region 2 domain-containing phosphatase 1 (SHP1) is implicated in immune regulation, its role in tumor malignancy remains unclear. Here, we demonstrate that SHP1 is significantly upregulated in CRC tissues and correlates with poor prognosis. Mechanistically, SHP1 was found to dephosphorylate the N(6)-methyladenosine (m6A) demethylase fat mass and obesity-associated protein (FTO) at the Y475 tyrosine residue, thereby enhancing its enzymatic activity to reduce global m6A methylation levels. Integrated RNA sequencing and m6A profiling revealed that SHP1 depletion increased PTEN-induced kinase 1 (PINK1) mRNA m6A modifications, promoting its degradation and suppressing mitophagy. SHP1 inhibitor TPI-1 or siRNA-SHP1-loaded lipid nanoparticles (LNPs) attenuated CRC cell proliferation, migration, and tumor growth in xenograft models through impaired mitochondrial homeostasis. These findings establish the SHP1-FTO-m6A axis as a critical regulator of mitophagy-driven CRC progression. Clinically, our study highlights SHP1 as a prognostic biomarker and potential therapeutic target, with TPI-1 and LNP-siSHP1 offering novel strategies for CRC management.

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