Heatstroke (HS) represents a life-threatening hyperthermic emergency that often leads to multiple organ dysfunction syndrome (MODS), yet no specific pharmacotherapy exists to interrupt this progression. Recent evidence has identified ZBP1-mediated programmed necrosis as a key contributor to organ failure in severe HS, highlighting the critical need for agents that can inhibit this pathway. This study aimed to investigate whether fibroblast growth factor 4 (FGF4) could mitigate HS-induced MODS and to clarify the underlying molecular mechanisms. Using complementary in vitro and in vivo models, along with gene knockdown, proximity ligation, and immunoprecipitation assays, this study indicates that FGF4 significantly reduces multi-organ injury caused by heat stress. Mechanistically, FGF4 interacts with its receptor to activate the AMPK signaling pathway, leading to the phosphorylation of HSF1 at Ser121, which impairs HSF1 nuclear translocation and transcriptional activity, ultimately decreasing ZBP1 expression and inhibiting ZBP1-dependent programmed necrosis. Given the short half-life of native FGF4, a major obstacle for clinical application, a sustained-release nano-liposomal formulation (FGF4-Nano) was engineered using DEPE-PEG2000. This nano-formulation maintains full bioactivity and demonstrates enhanced therapeutic efficacy in HS models, as evidenced by reduced tissue necrosis, improved liver and renal function, and diminished inflammatory damage. Collectively, this work positions FGF4 as a novel suppressor of ZBP1-mediated necrosis, elucidates the mechanistic basis for its actions, and introduces a nano-delivery strategy that significantly amplifies its anti-HS potential, setting the stage for a targeted therapeutic intervention in severe heatstroke.

Extreme heat events are increasing in frequency, duration, and severity, often with higher air pollution (AP) levels. The biological mechanisms underlying combined heat and AP exposures and the role of NLRX1 in pulmonary and cardiac dysfunction remain largely undefined. Nlrx1[+/+] and Nlrx1[-/-] female mice were exposed to filtered air/CTR, HT (36 °C), ultrafine carbon black (UfCB) + ozone (O3) (CB 2.5 mg/m[3] + O3 1 ppm), and HT + UfCB + O3 for 3 h. Pulmonary inflammation was evaluated by bronchoalveolar lavage, while cardiac function and strain were evaluated using Doppler echocardiography. Mitochondrial function was assessed through coupling assay and ETC complex activity measurements. Both at 2 and 24 h, Nlrx1[-/-] mice showed no adaptive physiological cardiac responses and demonstrated impaired mitochondrial function after heat-alone exposure. UfCB + O3-alone exposure induced a decrease in stroke volume and cardiac output and a decrease in cardiac mitochondrial complex III-V activities in both genotypes. Combined HT + UfCB + O3 resulted in a greater reduction in ejection fraction percentage and fractional shortening percentage, greater pulmonary neutrophilia, and a reduction in complex III-V activities at 24 h post-exposure in Nlrx1[-/-] mice compared to Nlrx1[+/+] mice. Moreover, Nlrx1[-/-] mice demonstrated a greater decrease in longitudinal and circumferential strain, indicating dyssynchronous contraction throughout the heart layers and mid-cavity segments. Collectively, our findings indicate that NLRX1 deficiency alters the acute physiological cardiopulmonary responses to HT and UfCB + O3.

Extreme temperatures are emerging as major climate-sensitive drivers of chronic cardiovascular disease (CVD). Global warming has increased the frequency, duration, and intensity of heatwaves, while substantial cold-related risk persists, particularly in poorly insulated and socioeconomically vulnerable settings. Together, non-optimal temperatures account for millions of deaths annually, with a large and growing share attributable to CVD. In this narrative review, we synthesize epidemiological, mechanistic, and systems-level evidence linking heat and cold exposure to chronic cardiovascular outcomes, with a focus on ischemic heart disease, stroke, heart failure, and arrhythmias. We first outline key temperature metrics, shifting climate patterns, and challenges in exposure assessment, including the roles of humidity, diurnal variability, and indoor versus outdoor environments. We then summarize the epidemiology of temperature, CVD associations across diverse regions, highlighting U- and J-shaped exposure-response curves and disproportionate impacts in low- and middle-income countries, older adults, and socioeconomically disadvantaged communities. Mechanistic sections examine how heat and cold drive autonomic imbalance, endothelial dysfunction, oxidative stress, inflammation, haemoconcentration, changes in coagulation, renal injury, and myocardial oxygen supply-demand mismatch. We further discuss modifying effects of air pollution, wildfires, dust storms, and medication use, including clinically relevant drug-heat interactions in patients with chronic CVD. Finally, we review heat-health and cold-health action plans, health-system resilience frameworks, and emerging research gaps spanning exposure science, mechanistic studies, vulnerable populations, and policy evaluation. Recognising non-optimal temperature exposure as a modifiable environmental risk factor for chronic CVD is essential. Integrating climate-informed prevention, clinical care, and adaptation strategies offers substantial and timely opportunities to reduce cardiovascular burden in a warming and increasingly unstable climate.

Heat stress (HS) is an increasingly prevalent environmental and exertional challenge. In severe cases, HS may progress to heatstroke, a life-threatening clinical syndrome characterized by severe hyperthermia, systemic inflammation, and multi-organ dysfunction. This review synthesizes evidence from laboratory rodent models and suggests that gut microbiota dysbiosis may act as a mediator and amplifier of HS-induced pathology. Across diverse rodent models, HS remodels the gut microbiota by reducing microbial diversity. These compositional changes are accompanied by decreased short-chain fatty acids, altered bile acid profiles, and increased lipopolysaccharide burden, although the specific metabolites affected vary across models. Causal evidence from fecal microbiota transplantation and gnotobiotic experiments supports microbiota-dependent amplification of intestinal barrier failure, hepatic inflammation, and neuroinflammation. In contrast, evidence for the gut-reproductive, gut-kidney, gut-heart, gut-muscle, and gut-adipose axes remains predominantly associative or derived from interventional correlations without formal causality testing. Targeting the gut-organ axis through probiotics, prebiotics, antioxidants, or functional amino acids offers promising but largely preclinical adjunctive strategies, with rapid cooling and supportive care remaining the foundation of heatstroke management. Future research should prioritize temporally resolved human studies, multi-omics integration, and causal validation to define the translational potential of microbiome-directed interventions.

Heat is a growing public health threat, yet seasonal variations in adaptation including air conditioning (AC) use remain poorly understood. We examined the modifying role of electricity consumption (EC), a proxy for air conditioning (AC) use, in the association between maximum temperature and ambulance transports for heat-related illness in the Tokyo Metropolitan Area. Daily ambulance transport data (June-September, 2015-2019), alongside maximum temperature and EC data, were analyzed across seven prefectures. Using a two-stage approach, we fitted quasi-Poisson regression models to estimate relative risks (RRs) per 1 °C increase in maximum temperature under high and low EC conditions, and pooled prefecture-month-specific estimates through multivariate meta-analysis. Attributable fractions (AFs) and attributable numbers (ANs) were also calculated. A total of 88,893 transports were analyzed. In June, higher risks were observed under high EC (RR = 1.37, 95%CI: 1.32-1.42) compared with low EC (RR = 1.28, 95%CI: 1.25-1.32). In July, the pattern reversed, with lower risks under high EC (RR = 1.33, 95%CI: 1.30-1.36) than low EC (RR = 1.39, 95%CI: 1.35-1.44). EC modified the association between heat and ambulance transport in both early summer months (p = 0.01 and 0.03, respectively), but not in August or September. Across months and EC strata, heat-attributable fractions ranged from 22.1% to 34.0%. The higher risks under high EC in June may have reflected delayed or insufficient air conditioning use, whereas the lower risks in July are consistent with a possible protective role of AC emerging as the season progresses. These findings underscore the need for early season adaptation measures.

Exertional heat stroke (EHS) induces thermoregulatory and inflammatory disturbances, yet whether core temperature (Tcore) responses are altered during subsequent passive heat exposure (PHE) remains unknown. Our purpose was to determine whether prior exposure to EHS or lipopolysaccharide (LPS)-induced systemic inflammation alters Tcore response during a subsequent PHE in mice. Receiver operating characteristic (ROC) curve assessment was performed as a secondary analysis to establish the ability of the Tcore response to discriminate animals previously exposed to EHS or LPS. Thirty-one female mice were assigned to three groups: control (CON), LPS, or EHS. Animals were implanted with a Tcore telemetry sensor. Three hours before the PHE, mice in the LPS group received a single intraperitoneal injection of LPS (100 µg·kg[-1]), whereas 24 h before the PHE, EHS mice underwent an EHS protocol at 37.5°C and 40% relative humidity. CON animals received no intervention. The PHE test consisted of 40 min exposure to a 40°C environment with Tcore continuously recorded. During PHE, EHS mice exhibited higher Tcore than CON and LPS mice at 10 min (CON: 39.7 ± 0.2°C; LPS: 39.4 ± 0.4°C; EHS: 40.6 ± 0.3°C; P < 0.001) and 20 min (P < 0.001). After 30 min, both EHS and LPS groups displayed higher Tcore relative to CON. ROC curve analysis demonstrated that a Tcore threshold of 40.8°C at 10 min yielded 69% sensitivity and 94% specificity for identifying prior EHS (P < 0.001). These findings demonstrate that prior EHS and LPS alter the Tcore response during subsequent PHE in mice.NEW & NOTEWORTHY Prior exertional heat stroke (EHS) altered core temperature (Tcore) responses during subsequent passive heat exposure (PHE) in mice. Systemic inflammatory stress induced by lipopolysaccharide (LPS) also altered Tcore, although with a distinct temporal profile compared with EHS. These findings demonstrate that both serious heat illness and inflammatory stress can disrupt Tcore responses during environmental heat exposure and establish a foundation for future mechanistic studies investigating recovery following physiological stress in mice.

Climate change is increasing the frequency and intensity of extreme heat events, raising concern about prenatal thermal exposure as a potential risk factor for fetal brain development and offspring neurodevelopment. This systematic review aimed to synthesize evidence on prenatal heat exposure, placental inflammatory or stress-response pathways, and fetal or offspring neurodevelopmental outcomes, while evaluating the placenta-brain axis as a proposed mechanistic hypothesis rather than an established causal pathway. A systematic literature search was conducted in PubMed/MEDLINE, Scopus, Web of Science, Google Scholar, and Embase from database inception to 30 June 2026. Human observational studies, animal experiments, and in vitro mechanistic studies were included when they examined prenatal thermal exposure in relation to either placental function and stress-response mechanisms or fetal-brain and offspring neurodevelopmental outcomes. Ambient environmental heat, infectious fever, behavioral or exogenous heat exposure, experimental maternal hyperthermia, and direct cellular or organoid thermal stimulation were considered separately because these exposures are not biologically equivalent. Across the included studies, distinct prenatal thermal exposures-including ambient environmental heat, infectious fever, behavioral or exogenous heating, and experimentally induced hyperthermia-were associated with congenital central nervous system anomalies, including neural tube defects, as well as later outcomes such as neurodevelopmental delay, language impairment, autism spectrum disorder, cerebral palsy, and altered child-brain morphology. The strongest and most consistent early-pregnancy signal concerned neural tube defects during the periconceptional and neurulation periods, whereas evidence for later neurodevelopmental outcomes identified more heterogeneous susceptibility windows across gestation. Experimental evidence suggested alterations in placental barrier function, glucocorticoid and serotonin-related signaling, inflammatory and oxidative pathways, myelination, apoptosis, and neural-progenitor development. However, only one included experimental study jointly assessed maternal heat stress, placental alterations, and fetal-brain-related outcomes, while the human studies did not measure placental mediators or perform mediation analyses. Evidence from non-heat inflammatory studies therefore provides only indirect mechanistic context. Overall, prenatal heat exposure may contribute to neurodevelopmental vulnerability through multiple direct and indirect pathways, including a biologically plausible but unproven placenta-brain framework. Prospective studies integrating individual-level heat assessment, placental biomarkers, standardized fetal-brain imaging, and longitudinal neurodevelopmental follow-up are required to test this hypothesis.

Occupational heatstroke frequently causes acute kidney injury (AKI). Myoglobin, released by exertional rhabdomyolysis, is the central nephrotoxic amplifier and may be physically removable by extracorporeal techniques. Yet the trials governing purification timing enrolled general intensive care populations whose injury biology differs. We aimed to integrate heatstroke-specific renal pathophysiology, novel AKI biomarker performance, and evidence on extracorporeal modalities. We then mapped the temporal cascade onto a biomarker-augmented framework for initiating blood purification during a narrative State-of-the-Art Review. Ten search blocks were run in PubMed/MEDLINE to 16 August 2026, yielding 16,443 unique records. Eligible sources reported human or animal data, consensus statements, or mechanistic evidence bearing on three questions: (i) how does heat injure kidneys? (ii) which biomarkers detect injury? and (iii) when blood purification should begin? Records without an English-language abstract or without retrievable full text were excluded and, ultimately, 95 discreate sources were retained. Four pathways operate on distinct timescales: direct thermal cytotoxicity, myoglobin-driven ferroptosis, inflammatory-coagulation amplification, and gut-derived endotoxemia. L-FABP has the only prospective heat-specific human data; [TIMP-2]·[IGFBP7] has the strongest critical care record but none in heatstroke. No biomarker is validated for predicting later chronic kidney disease in this population. No modality has been shown superior in a heatstroke-specific population, and only one clinical study reports outcomes in exertional heatstroke. We propose a provisional three-tier initiation framework anchored to myoglobin concentration and tubular injury biomarkers rather than creatinine alone. It is a structured hypothesis rather than validated guidance, and prospective biomarker-stratified trials in occupational settings are needed.

Heatstroke is a life‑threatening condition characterized by hyperthermia and systemic inflammatory response, often leading to multi‑organ dysfunction and high mortality. Despite advances in understanding its pathophysiology, effective targeted therapies remain limited. Recent studies have highlighted ferroptosis, an iron‑dependent, lipid peroxidation‑driven form of regulated cell death, as a critical mechanism in heatstroke‑induced organ injury. This review synthesizes current evidence on the role of ferroptosis in heatstroke, including key signaling pathways such as Hippo‑Yes‑associated protein‑acyl‑CoA synthetase long‑chain family member 4, dysregulated heat shock response, and antioxidant defense failure. The present study also explored potential ferroptosis‑related biomarkers and therapeutic strategies targeting this cell death pathway. Understanding ferroptosis in heatstroke not only unveils novel pathophysiological insights but also opens avenues for early diagnosis and targeted intervention.

Although differences between training and competitive contexts in table tennis are widely recognized, empirical evidence quantifying these differences remains limited. This study compared the technical-tactical characteristics of 40 training matches and 40 international competitions among Chinese National Youth Team U15 female players to provide evidence for training optimization. A mixed-method approach combining heat map visualization and Generalized Estimating Equations (GEE) was used to examine contextual differences and identify key factors associated with match-winning probability. Results showed that training and international matches exhibited similar individual technical-tactical indicators but differed substantially in placement-technique combinations and the influence of stroke sequences on winning probability. Training matches emphasized control of short areas, whereas international competitions showed greater use of backhand long-area attacks to initiate offensive play. In addition, early strokes were more influential in training matches, while later strokes played a greater role in international competitions. These findings indicate that current training matches may not fully replicate international competitive demands. Training should therefore enhance rally-transition tactics, offensive initiation, and competitive simulation to improve transferability to international competition.