¹The Fifth Affiliated Hospital of Sun Yat-sen University, Department of Neurology, Zhuhai, China, ²The Second Afiliated Hospital of Xinjiang Medical University, Department of Neurology, Urumuqi, China

Background: TDP-43 dysfunction is a central pathogenic factor in multiple neurodegenerative disorders. Emerging evidence suggests that metabolic impairment contributes to neuronal vulnerability; however, the impact of TDP-43 loss on neuronal lipid metabolism and energy production remains insufficiently characterized.

Aims & Objectives: This study aimed to investigate the effects of neuronal TDP-43 deficiency on triglyceride metabolism and cellular energy homeostasis, and to evaluate whether metabolic modulation can alleviate TDP-43–associated neurodegenerative alterations.

Method: Neuron-specific TDP-43 knockout mice were used to examine metabolic alterations in vivo, together with neuronal cell models with TDP-43 deficiency in vitro. Lipid droplet accumulation and triglyceride levels were assessed, along with the expression of enzymes involved in triglyceride catabolism and lipid transport to mitochondria. Cellular energy status was evaluated by ATP production. Pharmacological modulation was performed using chlorogenic acid in vivo, while triglyceride heptanoate supplementation was applied to neuronal cultures to assess effects on neuronal viability.

Results: Neuronal TDP-43 deficiency led to progressive neurodegenerative changes accompanied by marked lipid droplet accumulation and elevated triglyceride levels in both in vivo and in vitro models. Mechanistically, TDP-43 loss downregulated key enzymes involved in triglyceride catabolism and impaired lipid transport to mitochondria, resulting in reduced ATP production. Pharmacological intervention with chlorogenic acid partially restored triglyceride catabolism and improved cellular energy production in TDP-43–deficient mice. In parallel, triglyceride heptanoate supplementation significantly enhanced the viability of TDP-43–deficient neurons.

Discussion & Conclusions: These findings demonstrate that neuronal TDP-43 deficiency induces a disruption of triglyceride catabolism and energy metabolism, contributing to neurodegenerative vulnerability. Pharmacological modulation of lipid metabolism effectively improves energy supply and neuronal viability in TDP-43–deficient models. Targeting metabolic pathways may therefore represent a promising neuropharmacological strategy for TDP-43–associated neurodegenerative disorders.