YTHDF3 (YTH N6-Methyladenosine RNA Binding Protein F3)

YTHDF3 also shapes responses to targeted therapy, chemotherapy, and immunotherapy. This review synthesizes the biochemical underpinnings, network positioning, and functional spectrum of YTHDF3, and outlines opportunities for context-specific therapeutic intervention within the epitranscriptomic landscape.

Mechanistically, m6A at CHD9 enhances translation through YTHDF1 and YTHDF3, promoting CHD9-MYBBP1A interaction in the nucleoplasm, sequestrating MYBBP1A from the nucleolus and activating CDKN1A (p21)-associated tumor-suppressive signaling. Collectively, our study establishes a scalable framework for functional mapping of the m6A epitranscriptome and uncovers a mechanistic link between CHD9 m6A modification and tumor suppression, paving the way for systematic exploration of other RNA modifications in cancer.

Functional assays further demonstrate that YTHDF3 knockdown enhances cisplatin sensitivity in bladder cancer cells and xenograft tumors, whereas enforced expression of KDM6B or CDKN1A phenocopies the cisplatin-sensitizing effect of YTHDF3 knockdown. Collectively, our findings define a lactate-AARS2-YTHDF3-KDM6B-CDKN1A axis that integrates metabolic reprogramming, m6A-dependent epitranscriptomic regulation, and epigenetic chromatin remodeling to drive cisplatin resistance in bladder cancer.

Reversible resistance to NVP-BEZ235 in ccRCC is driven, at least in part, by an m6A-dependent YTHDF3-SYNM axis. Targeting YTHDF3 or SYNM may provide a rational strategy to overcome PI3K/mTOR inhibitor resistance in ccRCC.

METTL14 knockdown remits HG-induced HK-2 cell apoptosis, inflammation, and ferroptosis via promoting SLC40A1. In addition, E2F4 enhances SLC40A1 transcription. This research provides new potential targets and insights for the treatment of DN.

Moreover, we demonstrated that the high-risk factor AC129507.1 in the lncRNA signature was a novel target of the m6A regulatory axis WTAP/YTHDF3/ALKBH5, and depletion of AC129507.1 could markedly induce ferroptosis in GC. Collectively, these findings provide a candidate strategy for risk classification and better clinical management of GC and shed new insight into the underlying mechanism of AC129507.1 in GC development.

Moreover, inhibition of INCENP and CDCA8 enhances NACT sensitivity by promoting multipolar spindle formation. Collectively, our findings establish that INCENP and CDCA8 serve as crucial biomarkers for predicting NACT responsiveness and as potential therapeutic targets for combination therapy with NACT to improve patient survival.

Finally, dual-luciferase reporter assays confirmed that circAGFG1 acts as a sponge for miR-1299, thereby potentially modulating the miR-1299 signaling pathway. Collectively, our findings delineate the critical role of the circAGFG1 in promoting TNBC progression, highlighting its potential as a novel therapeutic target.

Collectively, our findings unveiled that YTHDF3-mediated upregulation of STAT3 suppresses the type I ISG expression, thus promoting HPV carcinogenesis and establishing an ITME. Taken together, our results suggest that targeting the YTHDF3/STAT3/IRF7 axis could be a promising therapeutic strategy against HPV-associated malignancies.

In this study, our findings show that TRIM2 acts as an m6A-modified substrate of YTHDF3, promoting P53 protein degradation through the ubiquitin-proteasome system. Notably, silencing TRIM2 effectively reduced the tumorigenic effects of YTHDF3 in UVM.

High-risk patients exhibited heightened sensitivity to targeted therapies (e.g., dasatinib and olaparib), suggesting actionable therapeutic vulnerabilities. Functional studies identified YTHDF3 as a novel oncogenic driver that is significantly overexpressed in AML, where its knockdown suppressed proliferation, induced apoptosis, and stabilized leukemogenic transcripts (ZZZ3, KLHL11) via the regulation of mRNA stability. This integrative study reveals the m6A reader network as a central orchestrator of AML progression, provides a validated prognostic framework for risk-adapted therapy, and positions YTHDF3 as a potential diagnostic and therapeutic target, bridging RNA epigenetics with clinical translation in AML.

Circ_EPHB4 and YTHDF3 promote glioma progression by jointly targeting the Wnt3 signaling pathway, which may provide a new therapeutic strategy for gliomas.