Beyond ubiquitination the expanding regulatory network of TRIM proteins in endometrial disorders and cancer

Abstract Endometrial disorders comprise a biologically connected disease spectrum that extends from endometriosis (EMs) and endometrial hyperplasia (EH) to endometrial carcinoma (EC) and together they impose a considerable health burden on women worldwide. Although these conditions differ in pathological features and clinical presentation, they remain linked through dynamic crosstalk among hormonal signaling, inflammatory remodeling, immune regulation, metabolic adaptation, and genomic instability during disease progression. An important unresolved issue is how these regulatory layers interact and become integrated as benign lesions evolve toward malignant transformation. In this Review, we move beyond the conventional interpretation of tripartite motif (TRIM) proteins as merely E3 ubiquitin ligases and instead propose a disease-continuum framework that defines them as context-dependent and multidimensional integrative hubs in endometrial pathology. Rather than offering a simple protein-by-protein summary, we synthesize evidence from EMs and EH or endometrial intraepithelial neoplasia (EIN) and EC, and in doing so we show that TRIM proteins connect endocrine signaling with epigenetic plasticity and immune microenvironment remodeling and metabolic reprogramming and genome stability through both ubiquitin-dependent and ubiquitin-independent mechanisms. Within this conceptual framework, individual TRIM members display stage-specific and context-sensitive activities and thereby influence precancerous lesion development and lineage plasticity and immune escape and metastatic progression and therapeutic resistance. By integrating evidence across the endometrial disease spectrum, this Review identifies shared regulatory patterns and stage-associated network rewiring and also emphasizes the translational relevance of TRIM proteins as diagnostic and prognostic biomarkers and mechanistic stratifiers and candidate therapeutic targets. Taken together, this perspective supports a conceptual shift in which TRIM proteins are understood not simply as ubiquitin ligases but rather as integrative regulators of endometrial disease evolution, thereby offering a framework for future studies on precancerous interception and molecular stratification and precision therapy.