Heatstroke Depletes a Heart-Protective Lipid, and Restoring It Saves Mice

Heatstroke is one of the most dangerous consequences of extreme heat, and its deadliest complications are often cardiac. When core body temperature climbs above 40.5 degrees Celsius, the heart’s pumping efficiency deteriorates, blood pressure collapses, and mortality rises sharply. Yet beyond aggressive cooling and circulatory support, clinicians have few tools to protect the heat-stressed myocardium directly. A new study published in Experimental & Molecular Medicine now identifies a surprising molecular ally: Maresin1, a fat-derived signaling molecule that the body normally produces to wind down inflammation. The research, led by a team at Wenzhou Medical University in China, shows that heatstroke drains this lipid mediator from the blood and heart, and that replenishing it through a specific receptor on cardiomyocytes can rescue cardiac function and improve survival in mice.

Maresin1 belongs to a family of specialized pro-resolving mediators, compounds derived from omega-3 polyunsaturated fatty acids that macrophages release during the resolution phase of inflammation. Unlike drugs that simply suppress immune activity, these mediators actively orchestrate the cleanup: they curb inflammatory cytokine release, promote clearance of cellular debris, and support tissue repair. Previous work had implicated Maresin1 in protection against pulmonary hypertension, myocardial infarction, neurodegeneration, and metabolic disease, but its role in heatstroke had never been systematically examined, and it was unclear which receptor actually carried its cardioprotective signal inside the heart.

To find out, the researchers first built a mouse model of classical heatstroke by exposing animals to 39 degrees Celsius at 60 percent relative humidity for two hours in a climate chamber. Core body temperature, tracked with rectal thermocouples, climbed to roughly 43 degrees. Twelve hours later, plasma levels of liver enzymes and a battery of cardiac injury markers, including creatine kinase, lactate dehydrogenase, cardiac troponin I, and NT-proBNP, were significantly elevated. Echocardiography revealed a progressive decline in cardiac performance, with hallmark signs of diastolic dysfunction: elevated E/A and E/e’ ratios and reduced aortic and pulmonary arterial flow velocities. Histology showed cytoplasmic vacuolation in cardiomyocytes, a clear sign of cellular distress.

The team then used ultra-performance liquid chromatography coupled with tandem mass spectrometry to profile lipid mediators in plasma and cardiac tissue. Maresin1 levels dropped markedly six and twelve hours after heatstroke, suggesting that its depletion might contribute to the cardiac deterioration. At the same time, flow cytometry and immunofluorescence showed that leucine-rich repeat-containing G-protein-coupled receptor 6, or LGR6, a known receptor for Maresin1, was upregulated specifically in cardiomyocytes. The pattern looked like a compensatory stress response: the protective ligand was disappearing while the heart cranked up its receptor, apparently trying to capture whatever Maresin1 remained.

Next came the therapeutic test. Mice received Maresin1 by tail vein injection at doses ranging from 2 to 10 milligrams per kilogram after heatstroke induction. Treatment significantly improved survival, with 8 milligrams per kilogram emerging as the optimal dose, since 10 milligrams offered no additional benefit. Treated animals showed reduced cardiac injury biomarkers, less Nppa stress-gene expression, improved tissue architecture on staining, and better echocardiographic measures of diastolic function and blood flow. The lipid mediator was not merely an anti-inflammatory bystander; it was measurably repairing the heat-damaged heart.

The critical question was whether LGR6 was the conduit for this protection. The researchers generated global Lgr6-knockout mice, which under normal conditions had hearts indistinguishable from wild-type animals. After heatstroke, however, the knockout mice fared dramatically worse, with exaggerated cytoplasmic vacuolation, aggravated cardiac dysfunction on echocardiography, and higher mortality. Crucially, giving Maresin1 to these receptor-deficient mice produced no benefit at all: survival, biomarkers, and cardiac function were unchanged. A complementary experiment using a viral approach to knock down LGR6 specifically in cardiomyocytes confirmed the same picture, showing elevated troponin and NT-proBNP, more fibrosis and inflammation, and reduced ejection fraction after heatstroke. Without the receptor, the lipid’s power vanished.

Genome-wide RNA sequencing of left ventricular tissue pointed to the mechanism. Heatstroke shifted the cardiac transcriptome toward reactive oxygen species metabolic processes, and Maresin1 treatment reversed this signature while restoring pathways governing ATP metabolism. Transmission electron microscopy made the damage visible: heat-exposed hearts showed disorganized myofibrils, chromatin marginalization, swollen mitochondria with fragmented or lost cristae, and ruptured outer membranes. Maresin1 preserved mitochondrial structure and restored cardiac ATP content, while also suppressing malondialdehyde, a marker of lipid peroxidation and oxidative damage.

In cultured primary mouse cardiomyocytes exposed to 39 degrees, Maresin1 at 200 nanomolar concentration restored mitochondrial membrane potential, reduced mitochondrial reactive oxygen species measured with MitoSOX Red, normalized mitochondrial abundance, and improved oxygen consumption rates on a Seahorse XF-96 analyzer, including maximal respiration and ATP-linked respiration. At the molecular level, the treatment increased PGC1α, the master regulator of mitochondrial biogenesis, along with the downstream nuclear respiratory factors NRF1 and NRF2. A dual-luciferase reporter assay showed that Maresin1 enhanced PGC1α promoter activity, but this effect was abolished when LGR6 was silenced with siRNA, pinning the transcriptional boost to the receptor. Interestingly, NRF1 and NRF2 rose downstream of PGC1α as a secondary consequence of improved mitochondrial biogenesis rather than as direct targets of LGR6 signaling.

The stress-dependence of this pathway is one of the study’s most intriguing findings. Under sham conditions, deleting LGR6 did not perturb baseline cardiac function or the basal expression of mitochondrial biogenesis factors. Only under the double assault of hyperthermia and oxidative stress did cardiomyocytes become dependent on the Maresin1–LGR6 axis to sustain PGC1α-driven mitochondrial renewal. The authors interpret the heatstroke-induced upregulation of LGR6 as an adaptive mechanism that sensitizes the heart to available pro-resolving ligands precisely when they are needed most, a paradigm consistent with the context-dependent behavior of many G-protein-coupled receptors.

The clinical implications are tantalizing but tempered by caveats. Low Maresin1 levels have been reported in human conditions ranging from rheumatoid arthritis to type 2 diabetes and diabetic foot ulcers, suggesting that measuring this lipid could serve as a warning sign in severe heat illness. If human studies confirm the mouse findings, Maresin1 or drugs that activate LGR6 could become the first targeted therapy for heatstroke-induced cardiac dysfunction, a condition currently managed only with cooling and supportive care. For now, the work rests on animal models and global knockout approaches, and the authors note that cardiomyocyte-specific knockout studies and human translational research will be needed before the Maresin1–LGR6 axis can move toward the clinic. Still, in a warming world where heat-related deaths are climbing, the discovery that the heart’s own resolution chemistry can be harnessed against heatstroke offers a genuinely new therapeutic direction.

Subject of Research: The cardioprotective role of the Maresin1–LGR6 signaling axis in heatstroke-induced cardiac dysfunction

Article Title: Maresin1 improves cardiac dysfunction via LGR6 in heatstroke

Article References: Maresin1 improves cardiac dysfunction via LGR6 in heatstroke. (n.d.). https://doi.org/10.1038/s12276-026-01853-6

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01853-6

Keywords: heatstroke, Maresin1, LGR6, cardiac dysfunction, mitochondria, PGC1α, oxidative stress, lipid mediators, inflammation resolution, cardiomyocytes, ATP synthesis, mouse model