Emerging roles of TRIM in metabolic regulation

Recent findings have broadened our understanding of the tripartite motif (TRIM) protein family, positioning these proteins as pivotal regulators of cellular metabolism and cell fate. Primarily functioning as versatile E3 ubiquitin ligases, TRIM proteins orchestrate key metabolic pathways-including glucose, lipid, and amino acid metabolism-through both ubiquitination-dependent and -independent mechanisms such as oligomerization and epigenetic modification. For example, TRIM38, TRIM11, and TRIM24 have been reported to modulate glycolytic flux and insulin signaling by targeting key glucose transporters and glycolytic enzymes, with effects on cancer metabolism and insulin responses in model systems. Similarly, TRIM21 and TRIM56 have been implicated in fatty acid synthesis, oxidation, and cholesterol balance, with potential relevance to fatty-liver conditions and atherosclerosis. Moreover, TRIM-mediated regulation of amino acid metabolism-particularly through pathways involving glutamine and branched-chain amino acids-plays a central role in tumor metabolic reprogramming and survival. Beyond enzymatic regulation, TRIM proteins exert non-canonical functions through epigenetic modulation and interactions with signaling networks. This review synthesizes current insights into the multifaceted roles of TRIM proteins in metabolic control and cell death, suggesting that ferroptosis may link TRIM proteins to lipid and amino acid metabolism, and highlights the connection between TRIM proteins and metabolic stress as a key area for future research.