Trilobatin combats copper overload-induced cognitive impairment by blocking FDX1-dependent cuproptosis and restoring mitochondrial dynamics

Copper homeostasis disorder triggers neuronal cuproptosis and progressive cognitive degeneration, lacking effective natural therapeutic agents. Trilobatin (TLB), a dihydrochalcone from Lithocarpus polystachyus Rehd., was reported to inhibit FDX1, yet its systematic neuroprotective mechanism against copper overload remains unclear. Herein, chronic CuSO ₄ gavage mouse model and CuSO ₄ -exposed HT22 hippocampal neurons were constructed. Behavioral tests confirmed TLB dose-dependently rescued copper-induced memory deficits. Mechanistically, TLB bidirectionally regulated copper transporters SLC31A1/ATP7B to reduce intracellular copper deposition, alleviated oxidative stress, restored mitochondrial fusion-fission balance and ultrastructural integrity. TLB suppressed FDX1-driven cuproptotic signaling, normalized disrupted TCA cycle and mitochondrial respiratory function. FDX1 siRNA knockdown further verified FDX1 as the indispensable mediator of TLB’s neuroprotection. Collectively, TLB ameliorates copper overload-mediated hippocampal injury and cognitive dysfunction by inhibiting FDX1-dependent cuproptosis and restoring mitochondrial metabolism, offering a promising candidate for metal dyshomeostasis-related neurodegenerative diseases.