Abstract

Background Parthanatos, a distinct form of programmed cell death, has been implicated in tumour progression, yet its role in breast carcinoma (BRCA) remains unclear. Methods Transcriptomic and clinical data from public cohorts were analysed to quantify parthanatos activity using single-sample gene set enrichment analysis based on curated gene signatures. Multiple survival modelling strategies were compared, with the optimal model identified through cross-validation and independent cohort verification. Genomic alterations, copy number variation, and tumour mutation burden were assessed. AIFM1 expression was further investigated using single-cell and spatial transcriptomics, functional enrichment analyses, and immune landscape profiling. Cell and animal experiments were conducted to further investigate the function of AIFM1 in BRCA. Results Parthanatos activity was elevated in patients with BRCA and correlated with advanced stage, metastasis, and poor survival. The stepwise Cox (forward) model achieved the best prognostic performance across datasets. High parthanatos scores were associated with higher tumor mutation burden (TMB), distinctive mutation patterns, and increased CNV burden. AIFM1 expression correlated with copy number gains and genomic instability and was enriched in malignant cell populations. High AIFM1 expression was linked to the cell cycle and DNA repair pathways but inversely associated with metabolic processes. Immune profiling revealed reduced M1 macrophages, chemokines, tertiary lymphoid structures, interferon-γ, and cytotoxicity in the high-AIFM1 group. Functional experiments confirmed that AIFM1 promoted the proliferation and angiogenesis abilities of BRCA cells in vitro and promoted tumour growth in vivo. Conclusions Parthanatos is upregulated in BRCA and predicts poor prognosis. AIFM1 has emerged as a pivotal biomarker correlated with genomic instability and immune suppression, indicating its potential for prognostic and therapeutic applicati