Single-cell transcriptomics uncover RNF130-mediated TNF-α pathway activation and worenine synergy with paclitaxel in breast cancer.

[BACKGROUND] Triple-negative breast cancer (TNBC) is distinguished by high invasiveness and a tendency for recurrence. Recent studies have suggested that E3 ubiquitin ligases play a crucial role in the initiation and progression of various tumors. However, there is still an absence of systematic understanding regarding the specific function and molecular mechanisms of its member gene RNF130 in TNBC.

[METHODS] This study conducted a comprehensive analysis of large-scale transcriptomic data from databases such as TCGA and GEO. Additionally, single-cell RNA sequencing data from multiple breast cancer samples and their liver metastases were analyzed to evaluate the expression pattern, prognostic significance, and potential regulatory role of RNF130 in the tumor microenvironment. The effects of RNF130 on breast cancer cell proliferation, apoptosis, and chemotherapy sensitivity were explored through in vitro cell experiments and in vivo mouse models. Furthermore, the study screened and evaluated the targeted inhibitory effect of the Traditional Chinese Medicine active component Worenine on RNF130, as well as its combined therapeutic effect with paclitaxel.

[RESULTS] The findings indicated that RNF130 was notably overexpressed in breast cancer tissues and associated with unfavorable patient survival outcomes. Single-cell transcriptomic analysis revealed that RNF130 was predominantly enriched in malignant epithelial cell populations and closely associated with tumor immune evasion phenotypes. RNF130 knockdown inhibited proliferation, induced apoptosis, reduced TNF-α pathway activation, and enhanced sensitivity to paclitaxel, whereas RNF130 overexpression exerted the opposite effects. Co-culture experiments further demonstrated that RNF130 depletion promoted M1 macrophage polarization while control cells induced M2-like phenotypes. Additionally, Worenine downregulated RNF130 expression and displayed a synergistic inhibitory effect with paclitaxel.

[CONCLUSION] This study identifies RNF130 as a critical mediator of TNBC progression that regulates tumor growth, apoptosis, immune evasion, and metabolic reprogramming, partly through activation of the TNF-α signaling pathway. Furthermore, Worenine was found to reduce RNF130 expression and enhance the antitumor effect of paclitaxel, suggesting its potential utility in combination therapy for TNBC. These findings provide mechanistic insights into RNF130-driven malignancy and offer a foundation for developing future therapeutic strategies.