Harnessing lipid metabolism to surmount treatment resistance in aggressive non-Hodgkin lymphoma: from regulatory networks to novel therapeutic opportunities

Abstract Treatment resistance remains a major clinical challenge in aggressive non-Hodgkin lymphoma (aNHL). Resistance does not arise from a single dominant pathway. Instead, it reflects a redundant and adaptable network involving intracellular signaling, epigenetic regulation, ferroptosis evasion, remodeling of the tumor microenvironment, failure of cellular immunotherapy, and signals from the gut microbiota. Across B-cell and T-cell lymphomas, these mechanisms interact with lipid metabolic reprogramming. In this review, we position lipid metabolism as a downstream convergence node within this broader resistance network. Changes in fatty acid synthesis and oxidation, cholesterol homeostasis, membrane lipid composition, and lipid peroxidation allow tumor cells and their surrounding microenvironment to integrate survival signals, maintain metabolic fitness, promote immune evasion, and withstand treatment pressure. We discuss how this framework centered on lipid metabolism relates to resistance against chemotherapy, targeted agents, immune checkpoint blockade, and CAR T-cell therapies. We then assess therapeutic opportunities offered by lipid-modulating agents, especially clinically established drugs such as statins, fatty acid synthesis inhibitors, and fatty acid oxidation modulators. Their known pharmacological profiles and potential compatibility with standard lymphoma treatments make drug repurposing an attractive strategy. At the same time, the current evidence base remains uneven. Most mechanistic and combination data come from preclinical lymphoma models, small patient cohorts, other hematologic malignancies, or solid tumors. Direct causal evidence and prospective clinical validation in aNHL remain limited. This gap also defines the novelty of this review. By systematically integrating available preclinical findings with clinical and translational evidence from related disease settings, this review provides a practical reference framework for future aNHL studies and may accelerate clinical evaluation of lipid metabolic targeting as a feasible approach to overcoming treatment resistance.