Traumatic brain injury (TBI) induces direct mechanical injury and secondary injury processes, among which ferroptosis, a regulated and iron-dependent form of cell death, has emerged as a key mechanism. Circadian clock disruption is also commonly described in TBI patients and is reported to exacerbate pathological outcomes of TBI. However, the crosstalk between circadian clock dysfunction and ferroptosis in TBI remains unclear. Using a mouse TBI model, disrupted expression of core circadian clock regulators BMAL1, CLOCK, and PER2 was observed, accompanied by iron accumulation, blood-brain barrier (BBB) leakage, and neuronal damage. Ferroptosis inhibitors, melatonin (MLT) and liproxstatin-1 (Lip-1), alleviated TBI-induced weight loss and neurological dysfunction. In contrast to MLT, Lip-1 failed to rescue body temperature rhythmicity, although both agents modulated the circadian clock at the molecular level. Mechanistically, the Bmal1 downregulation sensitized HT-22 neurons to RSL3-induced ferroptosis in vitro by exacerbating oxidative stress and iron overload. Collectively, these findings demonstrated an asymmetric crosstalk, in which circadian clock disruption promotes ferroptosis, and inhibition of ferroptosis feeds back to modulate clock gene expression without restoring behavioral rhythms. This circadian-ferroptosis axis may represent a novel and promising target for therapeutic intervention in post-TBI neuroprotection.
