ALYREF (Aly/REF Export Factor)

Mechanistically, we found that ALYREF is a methylation recognition protein that directly and specifically recognizes the m5c site of BNIP3 mRNA and enhances the stability of BNIP3 mRNA, which activates autophagy in prostate cancer cells, and thus enhances the anoikis resistance and metastatic ability of cancer cells. Overall, our study revealed the important role of ALYREF-mediated m5C methylation modification in the mechanisms of autophagy and anoikis resistance in prostate cancer, providing an important molecular target for the treatment of advanced prostate cancer.

The ALYREF-ZWINT axis promotes CD4+ T cell ferroptosis, contributing to an immunosuppressive microenvironment and facilitating tumor progression in COPD-associated NSCLC. Targeting this pathway represents a novel therapeutic strategy to restore anti-tumor immunity.

Overall, our study suggested that ALYREF drove LC progression by stabilizing DDX11 mRNA. The findings provided novel insights into the role of ALYREF-induced m5C modifications in LC, opening up new perspectives for further research.

In vivo experiments demonstrated that ALYREF knockdown suppressed tumor growth and lung metastasis, while SCD overexpression reversed the tumor-suppressive effects of CASC19 knockdown. In Conclusion, this study unveils the pivotal regulatory role of the ALYREF/m5C/CASC19/HNRNPC/SCD axis in CRC, providing a novel therapeutic target for disrupting RNA epigenetic-metabolic interactions in cancer treatment.

Moreover, NSUN2 is transcriptionally activated by the YAP-TEAD2 complex, forming a positive feedback loop that promotes tumor growth and metastasis, a process effectively suppressed by m5C inhibitors both in vivo and in vitro. Furthermore, our presented findings suggest that NSUN2 promotes tumor growth and metastasis by increasing ALYREF/YBX1-mediated YAP expression in NSCLC and effective inhibition of m5C modification might provide a potential treatment strategy for NSCLC.

Our findings indicate that ALYREF promotes tumor progression by enhancing glycolysis. Glycolysis-derived lactate stabilizes the ALYREF protein via lactylation at K171, establishing a positive feedback loop that drives LC malignancy. Silencing ALYREF suppresses tumor growth, underscoring its potential as a therapeutic target in LC.

m5C modifications are globally altered in HBV-negative HCC and may contribute to post-transcriptional regulation and aberrant expression. These findings highlight the potential of m5C as both a prognostic biomarker and a therapeutic target in HBV-negative HCC.

Meanwhile, reader proteins YBX1 and ALYREF maintain the stability of m5C-modified RNAs and activate proliferative and pro-invasive signaling pathways, including PI3K/AKT, mTOR, and Hippo/Wnt. In addition, m5C plays a pivotal role in shaping the tumor immune microenvironment and modulating immune checkpoint activity, thereby influencing the responsiveness and resistance of lung cancer to radiotherapy, chemotherapy, targeted therapy, and immunotherapy.

Our study established lactylation modifications as a crucial regulator of the TME and glioma progression. Through integrative multi-omics analysis and robust machine learning techniques, we determined that RAN was a novel lactylation-associated gene. RAN is a potent, independent prognostic biomarker that promotes glioma malignancy via the PI3K/AKT pathway. Our results demonstrate RAN as a prospective therapeutic target and establish a novel framework for individualized therapy for glioma.

In this study, we integrated RNA-Seq and single-cell transcriptomic data from cisplatin-resistant ovarian cancer cell lines and patient samples, identifying the m5C reader protein ALYREF as a key regulator of platinum resistance...Together, our findings demonstrate that the NSUN2/ALYREF/LGR4 axis mediates platinum resistance through m5C-dependent stabilization of LGR4 and downstream Wnt signaling activation. Thus, targeting ALYREF may represent a promising strategy to overcome platinum resistance in ovarian cancer.

Finally, ALYREF and PARP10 expression correlate with poor prognosis in ovarian cancer patients. Together, these findings suggest that ALYREF phase separation facilitates the malignant progression of ovarian cancer by promoting PARP10 expression and thereby enhancing PARP10-dependent proliferative pathways in a m5C-dependent manner.