Circulating Neuregulin-4 tracks acute hyperbaric and workload stress in human divers, preceding oxidative injury markers

Acute hyperbaric stress during diving combines increased ambient pressure, hyperoxia, hemodynamic shifts, and often muscular workload. Identifying real-time blood biomarkers sensitive to these individual and combined physiological loads remains a challenge. Neuregulin-4 (NRG4), an adipokine secreted by thermogenic and subcutaneous white fat, responds to adrenergic stimulation and modulates redox homeostasis. We investigated NRG4 dynamics alongside oxidative protein carbonyls in divers in warm (thermoneutral) water (∼33.6 °C ambient water temperature) to avoid cold stress. Two field campaigns were conducted: a first depth response campaign involved divers exposed to 20, 30, or 40 m on separate days, without exercise, with serial blood sampling; a second physical effort study involved 15 m dives with or without slow-pedalling exercise. Serum NRG4 was quantified by ELISA and expressed as log2 fold change relative to baseline. Protein carbonyls were measured as markers of oxidative damage. Statistical analysis employed single-sample tests and false-discovery rate control. NRG4 exhibited a robust early increase at 30 m, significant after correction, and nominal elevations at 40 m, but remained unchanged at 20 m. Exercise at 15 m triggered a significant early NRG4 rise absent during passive dives at the same depth. Protein carbonyls remained stable in early post-emersion windows but increased significantly at later time points (180- and 240-min post-emersion) following dives to 40 m, indicating delayed oxidative burden. Our findings position NRG4 as a fast, pressure- and workload-responsive biomarker of diving stress, temporally distinct from classical oxidative injury markers that manifest later. This temporal dissociation underscores the potential of NRG4 for real-time monitoring of acute physiological load during hyperbaric exposure, integrating pressure- and workload-related stressors.