Abstract
BACKGROUND: FAT10 is an inflammation-induced oncogene highly overexpressed across multiple cancers. As a ubiquitin-like protein, it regulates interacting proteins by destabilizing, stabilizing or delocalizing them. Despite its extensive influence on targets from various cellular pathways, prior studies largely focused on interrogating individual protein interactions, limiting our understanding of FAT10’s broader oncogenic role. METHODS: Here, we adopt a novel systems-level approach to elucidate FAT10’s function by integrating quantitative proteomics, interactomics and metabolomics analyses in a cancer cell model. Biochemical methods including western blot, Seahorse Assay and Oil-Red-O staining were used to validate FAT10’s impact on protein expression and metabolism in metabolism-related pathways. We further investigated the effect of metabolic stress on FAT10 expression by modulating metabolite levels or treatment with metabolic pathway inhibitors. FAT10-induced survival under metabolic stress and inflammation was assessed using Cell Counting Kit-8 assay and cleaved caspase 3 quantification. RESULTS: We demonstrate that FAT10 prominently regulates metabolism-related pathways, coordinately upregulating those involved in energy uptake, production and storage (glycolysis, lipogenesis and β-oxidation), while downregulating those in energy consumption (pentose phosphate pathway, nucleotide metabolism, transcription, translation and cell cycle) and truncating the TCA cycle. These changes indicate a potential shift from a replication-oriented to a survival-oriented cellular state. Correspondingly, metabolic stress promoted inflammation-induced FAT10 transcription. FAT10 consequently enhanced cancer cell survival under concurrent metabolic stress and inflammation. CONCLUSIONS: Overall, our findings establish FAT10 as an immunometabolic survival factor that responds to metabolic stress under inflammation, propagating global metabolic changes to alleviate this stress and promote cancer survival by potentially orchestrating a fundamental shift in cellular priorities from replication to survival. Through our systems-level perspective on FAT10's regulatory activities, we contextualize its previously disparate functions and reveal a potential blueprint for cellular survival programming of metabolism-related pathways during inflammation and stress. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12964-025-02513-4.