Nanocurcumin attenuates brain injury in rats with desert dry‑heat‑induced exertional heat stroke by suppressing TLR4/MyD88/NF‑κB signaling

Exertional heat stroke (EHS) is a life‑threatening condition characterized by hyperthermia, systemic inflammation and central nervous system injury, particularly in desert dry‑heat environments. Excessive activation of inflammatory signaling pathways, notably the Toll‑like receptor (TLR)4/myeloid differentiation factor 88 (MyD88)/NF‑κB axis, critically contributes to brain damage and neuroendocrine dysfunction in EHS. Curcumin exhibits anti‑inflammatory and neuroprotective effects; however, poor bioavailability limits its clinical application. Notably, nanocrystal formulations may improve the therapeutic efficacy of curcumin. In the present study, network pharmacology and molecular docking were employed to identify the potential therapeutic targets of curcumin in EHS. A rat model of desert dry‑heat‑induced EHS was established and nanocurcumin was administered intravenously following heat exposure. Histopathological examination, ELISA analyses of neuroendocrine hormones and inflammatory cytokines, serum biochemical assays and western blotting were subsequently performed. These evaluations assessed brain injury, hypothalamic‑pituitary‑adrenal and hypothalamic‑pituitary‑thyroid axes functions, systemic inflammation, peripheral organ injury indicators and activation of the TLR4/MyD88/NF‑κB signaling pathway. Network analysis revealed 138 overlapping target genes between curcumin and EHS, identifying AKT1, TNF, EGFR, BCL2, STAT3, SRC and NFKB1 as key hub genes. Kyoto Encyclopedia of Genes and Genomes pathway analysis highlighted enrichment of the ‘Toll‑like receptor signaling pathway’ and ‘NF‑κB signaling pathway’. Molecular docking indicated favorable binding affinities of curcumin to essential inflammatory proteins, including TLR4, MyD88 and NFKB1. In vivo experiments demonstrated that nanocurcumin reduced neuronal injury in the cerebral cortex and hypothalamus of rats. Furthermore, nanocurcumin significantly decreased serum concentrations of corticotropin‑releasing hormone, corticosterone, thyrotropin‑releasing hormone and thyroid‑stimulating hormone, and restored adrenocorticotropic hormone, total triiodothyronine and free triiodothyronine levels. Nanocurcumin also lowered serum TNF‑α, IL‑6 and IL‑1β levels, and improved biochemical markers of liver, kidney and tissue injury (alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, creatine kinase and lactate dehydrogenase). Within the 4‑h observation period, medium and high doses of nanocurcumin did not worsen biochemical markers compared with those in the EHS or saline groups. Additionally, nanocurcumin administration dose‑dependently inhibited TLR4, MyD88 and NF‑κB protein expression in brain tissues. In conclusion, nanocurcumin may alleviate brain injury, neuroendocrine dysfunction and systemic inflammation associated with desert dry‑heat‑induced EHS, and may improve biochemical indicators of peripheral organ damage; these effects likely involve suppression of the TLR4/MyD88/NF‑κB signaling pathway. These findings support the use of nanocurcumin as a promising adjunctive therapy for managing EHS.