The Neural Thermostat Malfunction: Revisiting Heatstroke Through the Lens of Warm-Sensitive Neuron Dysregulation

Xiaofeng Zhao^1,2Jie Zhu^3,4Qingqiu Tang²Zhu He⁵Zhifeng Liu^1,2*

• ¹The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
• ²Department of Medicine Intensive Care Unit, General Hospital of Southern Theater Command of PLA, Guangzhou, China
• ³Department of Pediatric, General Hospital of Southern Theater Command of PLA, Guangzhou, China
• ⁴Department of Pediatric, Daping Hospital, Army Medical University, Chongqing, China
• ⁵Department of Clinical Research Institute, Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang, China

Rising global temperatures have turned heatstroke from a seasonal concern into a year-round public health crisis, yet its underlying neuropathological mechanisms remain elusive. Central to this problem are hypothalamic warm-sensitive neurons (WSNs), the master regulators that integrate central and peripheral thermal signals. This review synthesizes recent advances linking the molecular architecture of WSNs to heatstroke pathophysiology. Emerging evidence redefines WSNs not simply as temperature sensors, but as putative neuromodulatory hubs that may coordinate neuroinflammation, blood-brain barrier (BBB) disruption, and multi-organ failure through hypothesized neurotransmitter-cytokine crosstalk. By mapping the functional hierarchy of WSNs—from molecular thermoregulation to systemic control of thermoeffectors—this work proposes targeted neurotherapeutic strategies, offering a novel neural circuit-based framework for managing heatstroke.