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bioRxiv · 10.64898/2026.02.12.692412

Fusion-driven post-transcriptional network orchestrates ferroptosis resistance, dormancy, and immune remodeling in PRCC-TFE3 renal cell carcinoma

Mishra, D.·Agrawal, S.·Malik, D.·Pathak, E.·Mishra, R.
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Abstract

TFE3-rearranged papillary renal cell carcinoma (pRCC) remains poorly understood due to its rarity and complex biology. By integrating matched mRNA and miRNA sequencing from the TCGA-KIRP cohort, this study reveals a fusion-specific post-transcriptional program orchestrating ferroptosis resistance, metabolic adaptation, adhesion loss, immune remodeling, and dormancy-associated signaling. Fusion-positive tumors exhibited coordinated upregulation of antioxidant and mTORC1 components (SOD2, GPX4, G6PD, NQO1, FNIP2, RRAGC), reinforced by loss of miRNA-mediated repression. In parallel, elevated miRNAs (miR-185, miR-148a, miR-130b, miR-342) suppressed MAPK, Wnt, and tight-junction genes, generating a low-proliferative, adhesion-deficient state. AGO2-compatible miRNA-mRNA structural modeling validated key duplexes, linking miRNA regulatory specificity to fusion-driven transcriptional outputs. Immune profiling revealed reduced CD3 T cells but enrichment of CD8 and NK cells, supporting a remodeled yet persistence-permissive microenvironment. Finally, connectivity mapping analysis identified candidate leads targeting the MAPK-Wnt axis. These findings define a multilayered RNA regulatory architecture unique to PRCC-TFE3 tumors.

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Mishra, D., Agrawal, S., Malik, D., Pathak, E., Mishra, R.. 2026-02-13. Fusion-driven post-transcriptional network orchestrates ferroptosis resistance, dormancy, and immune remodeling in PRCC-TFE3 renal cell carcinoma. https://doi.org/10.64898/2026.02.12.692412

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