YTHDF3 (YTH N6-Methyladenosine RNA Binding Protein F3)

Following treatment with temozolomide (TMZ), the level of m6A modification was increased, facilitating YTHDF3-mediated DNA damage repair...Mechanistically, YTHDF3 recognizes the m6A binding site of DNA damage response genes (BRCA1, RAD51, RIF1 and 53BP1) and promotes their translation through m6A methylation, thereby initiating homologous recombination (HR) and nonhomologous end joining (NHEJ) repair to resist endogenous and exogenous DNA damage. Consequently, our study elucidates the crucial role of YTHDF3 in GBM and provides valuable insights into its significance in the DNA damage response and chemoresistance.

Finally, this BGN/MDK axis could also drive the activation of normal fibroblasts into a CAF-like phenotype verified by vitro assays. In conclusion, the interplay between cancer cells and CAFs mediated by the BGN/MDK axis is a critical driver of malignancy in melanoma, highlighting it as a promising therapeutic target for intervention.

Using dCasRx-TRMT6, we further show that site-specific m1A deposition on DSN1 mRNA is a potent strategy to modulate its expression and drive proliferation. Collectively, our findings uncover a previously unrecognized m1A-dependent regulatory axis that underpins LUSC diagnosis and progression.

This METTL14-YAP1 axis activates CD166-EGFR-LOXL2 signaling, leading to enhanced collagen cross-linking and deposition, increased stromal stiffness, and maintenance of tumor stemness. These results identify the METTL14-YAP1 feedback loop as a core regulator of mechanical memory in pancreatic ductal adenocarcinoma, which drives stromal dysfunction and tumor progression through CD166-LOXL2 axis, and suggest targeting this loop as a potential therapeutic strategy to disrupt mechanical memory and ameliorate stiffness-induced remodeling.

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.