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

The central finding of the study is that heat stress reshapes the gut microbiome of mice in two complementary ways. First, the microbial disruption is accompanied by increased levels of lipopolysaccharide, or LPS, a potent inflammatory molecule embedded in the outer membrane of many gut bacteria. When the intestinal barrier weakens, LPS can slip into the bloodstream and activate immune cells throughout the body. Second, the team found that heat stress enhances microbial catabolism of arginine, an amino acid that the new work identifies as a natural brake on inflammatory signaling. In other words, heat does not just add fuel to the inflammatory fire; it removes one of the fire extinguishers at the same time.

To establish that these microbial changes are not merely a byproduct of heat injury but an active driver of it, the researchers performed fecal microbiota transplantation experiments. When they transferred gut microbes from heat-stressed mice into healthy recipient animals, the recipients went on to mount exaggerated inflammatory responses after experiencing heat stress themselves. This result provides some of the strongest causal evidence yet that the gut microbial alterations induced by heat are functionally responsible for worsening systemic inflammation, rather than simply correlating with it. It suggests that the microbiome acts as an intermediary that can be reprogrammed by environmental temperature and then transmit that reprogramming into immune consequences.

The mechanistic heart of the paper concerns how arginine protects tissues at the molecular level. Using cell culture experiments in macrophage-like RAW264.7 cells and microglial BV2 cells, the team showed that arginine reduces the abundance of MyD88, a key adaptor protein that sits at the crossroads of multiple innate immune signaling pathways. MyD88 physically interacts with Toll-like receptor 4, the receptor that recognizes LPS, and passes the alarm signal onward to the transcription factor NF-kB, whose p65 subunit must move into the nucleus to switch on genes encoding pro-inflammatory cytokines. The researchers found that arginine promotes ubiquitination of MyD88, the molecular tag that marks proteins for degradation, thereby lowering MyD88 protein levels. With less MyD88 available, the interaction between MyD88 and TLR4 weakens, p65 nuclear translocation is curtailed, and the expression of pro-inflammatory genes falls.

Experiments in living mice reinforced this mechanism. Pretreating animals with exogenous arginine significantly suppressed inflammation in the liver and in the cortex of the brain after heat stress, the two organs highlighted in the study as major sites of heat-related damage. When the researchers knocked down TLR4 or MyD88 in their cellular models, the protective effect of arginine was lost or blunted, indicating that the amino acid’s benefit depends on the very pathway it modulates. Taken together, the data sketch a coherent circuit: heat raises LPS and lowers arginine, LPS engages TLR4, and the resulting MyD88-dependent signaling cascade runs unchecked when arginine is scarce.

Importantly, the team did not stop at animal models. They examined serum samples from patients suffering from heatstroke and found that arginine levels were lower in these patients than expected. Moreover, the degree of arginine depletion was positively related to markers of liver injury and inflammation, meaning that patients with the least circulating arginine tended to show the worst clinical indicators. While the human component of the study is observational and cannot by itself prove causation, it aligns closely with the mouse and cellular data and raises the possibility that arginine status could serve as a biomarker for heatstroke severity or as a guide for nutritional intervention.

The translational ambition of the work culminates in a delivery system the authors developed to counteract the microbial imbalance: an arginine-enriched oral inulin hydrogel, abbreviated Arg_OIH. Inulin is a dietary fiber with prebiotic properties, meaning it can nourish beneficial gut microbes and help maintain microbial homeostasis. By embedding arginine within an inulin-based hydrogel, the researchers aimed to achieve two goals at once. The inulin component stabilizes the gut microbiota, which in turn reduces LPS levels, while the hydrogel matrix provides a sustained, slow release of arginine to keep the amino acid available to tissues over time rather than delivering a single spike that the body would quickly clear.

According to the study, this hydrogel formulation was able to prevent the inflammatory responses exacerbated by heat-induced gut microbial alterations, and the supplementary data document its characterization, its effects on the gut microbiota of heat-stressed mice, and histopathological evidence of tissue protection. The authors also compared the hydrogel against a simple oral arginine solution, suggesting that the sustained-release design offers advantages over free amino acid supplementation. If the approach can be translated safely to humans, it could offer a practical prophylactic strategy for vulnerable populations, such as outdoor workers, athletes, the elderly, and people living in regions where extreme heat events are becoming routine.

The study also carries broader conceptual weight for microbiome science. It adds to a growing body of evidence that the gut microbiome functions as a metabolic buffer between the environment and the immune system, converting external stressors into shifts in microbial chemistry that either calm or inflame the host. Here, the balance between LPS and arginine emerges as a previously underappreciated axis: one side pushes TLR4-MyD88 signaling toward inflammation, while the other restrains it through post-translational modification of a central adaptor protein. Disrupting that balance, as heat stress appears to do, converts a manageable physiological response into a self-amplifying inflammatory loop capable of damaging multiple organs.

Caveats remain, as they do in any preclinical study. The mouse models of heat stress, however carefully controlled, cannot fully reproduce the complex physiology of human heatstroke, and the clinical samples, while suggestive, came from a patient cohort whose characteristics are detailed in the study’s supplementary tables. The authors note that the published version was shared early as accepted peer-reviewed research, subject to final editorial processing. Nevertheless, the convergence of evidence across fecal transplantation, metabolomics, cellular signaling assays, genetic knockdown experiments, and human serum measurements gives the arginine-MyD88 axis a solid evidentiary foundation. As global temperatures continue their upward climb, interventions that restore gut microbial balance and replenish protective metabolites may become an increasingly important part of the public health arsenal against heat, and this study offers a concrete, mechanistically grounded starting point for developing them.

Subject of Research: Gut microbial arginine catabolism and LPS balance in heat stress-induced inflammatory responses

Article Title: Heat stress enhances gut microbial arginine catabolism to amplify MyD88-dependent inflammatory responses

Article References: Ye, X., Cai, Q., Pan, Y., Xu, M., Li, Y., You, M., Yang, J., Chen, S., He, H., Hong, G., & Zheng, H. (2026). Heat stress enhances gut microbial arginine catabolism to amplify MyD88-dependent inflammatory responses. Microbiome, 14(1), Article 215. https://doi.org/10.1186/s40168-026-02514-6

Image Credits: AI Generated

DOI: 10.1186/s40168-026-02514-6

Keywords: heat stress, gut microbiota, arginine, lipopolysaccharide, MyD88, TLR4, inflammation, heatstroke, inulin hydrogel, NF-kB, liver injury, metabolomics