BACKGROUND: Cardiorenal syndrome (CRS) is a complex condition characterized by the interplay between cardiac and renal dysfunction, often culminating in renal fibrosis. The role of macrophage polarization and its downstream effects in CRS-induced renal fibrosis remains an area of active investigation. METHODS: Single-cell RNA sequencing (scRNA-seq) and immune infiltration analyses were employed to identify key immune cells and genes involved in renal fibrosis in CRS. Meta-analysis and pseudo-time analysis were conducted to validate the functional relevance of these genes. Functional studies utilizing CRISPR/Cas9 gene editing and lentiviral vectors assessed macrophage polarization and epithelial-to-mesenchymal transition (EMT). In vivo, a CRS mouse model was established, and fibrosis progression was tracked using histological and imaging methods. RESULTS: The PKM2/mTORC1/YME1L signaling axis was identified as a critical pathway driving renal fibrosis, mediated by HIF-1α-induced M1 macrophage polarization. Inhibition of HIF-1α significantly alleviated renal fibrosis by restricting M1 polarization and suppressing the PKM2/mTORC1/YME1L axis. Co-culture models further demonstrated the involvement of EMT and metabolic reprogramming in affected cells. CONCLUSION: Targeting the HIF-1α signaling pathway offers a promising therapeutic strategy for renal fibrosis by modulating macrophage polarization and the PKM2/mTORC1/YME1L axis.