IFFO1 inhibits breast cancer by coordinating mitochondrial fission and fatty acid synthesis via the LaminA/C-PGC1α axis.

Accumulating evidence indicates that mitochondrial dynamics are closely linked to the biological behaviors of tumor cells, with increased mitochondrial fission being recognized as a phenotype that promotes tumor growth. Although intermediate filament family orphan 1 (IFFO1) has been implicated in mitochondrial dynamics, its specific role and molecular mechanisms in regulating mitochondrial fission during breast cancer (BC) progression remain unclear. In this study, analysis of tumor and adjacent normal tissues from 30 BC patients revealed significant downregulation of IFFO1 in tumor tissues, and low IFFO1 expression predicted poor prognosis in patients. In vitro experiments demonstrated that IFFO1 overexpression suppressed the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of BC cells by inhibiting mitochondrial fission and fatty acid synthesis. Mechanistically, IFFO1 interacts with LaminA/C to promote its expression, which subsequently upregulates PGC1α, thereby suppressing mitochondrial fission and fatty acid synthesis in BC cells. Consistent with this mechanism, both LaminA/C and PGC1α were downregulated in BC tissues. Silencing LMNA reversed the inhibitory effects of IFFO1 overexpression on mitochondrial fission and fatty acid synthesis, whereas overexpression of PGC1α effectively counteracted the consequences of LMNA knockdown. In vivo studies confirmed that upregulation of IFFO1 inhibited tumor growth in xenograft models and reduced lung metastasis in a lung metastasis mouse model. These findings underscore the significance of the IFFO1/LaminA/C/PGC1α pathway as a key regulator of mitochondrial fission and fatty acid synthesis during BC progression and highlight its potential as a therapeutic target for breast cancer.