Molecular hydrogen in cancer: reprogramming oncogenic signaling pathways and emerging pharmacological potential

Abstract

Molecular hydrogen (H 2 ) is a chemically inert, non-toxic, highly diffusible gas that has recently attracted considerable interest as a novel bioactive mediator with growing therapeutic relevance in oncology. Emerging evidence suggests that H 2 modulates multiple pathways involved in cancer initiation and progression, including attenuation of oncogenic signaling, suppression of metastatic dissemination, enhancement of therapeutic responsiveness, and regulation of epigenetic, mitochondrial, and immune-associated oncogenic programs. Beyond its antioxidant activity, H 2 has been shown to partially reprogram cancer-associated epigenetic modifications, restore dysregulated proteostatic pathways, and attenuate oxidative stress–driven cellular injury, collectively contributing to reduced tumor cell survival and enhanced therapeutic sensitivity. Recent preclinical studies demonstrate that H 2 exerts anticancer effects through coordinated regulation of epigenetic remodeling, mitochondrial stress and proteostasis, tumor suppressive cell death and cell-cycle arrest, and immunomodulation with metastatic restraint. Specifically, H 2 influences histone methylation dynamics and oncogenic non-coding RNA signaling, activates mitochondrial stress and unfolded protein response pathways, induces cell-cycle arrest and inflammatory tumor cell death, and suppresses metastatic behavior through the downregulation of key proliferation and immune evasion associated mediators. In parallel, H 2 based interventions have been shown to enhance antitumor immune responses by modulating CD8 + T-cell activity, apoptosis related regulators and tumor suppressor signaling across hepatocellular and lung cancer models. Collectively, these findings position H 2 as a pharmacologically versatile adjuvant with the capacity to enhance conventional anticancer therapies while mitigating oxidative and inflammatory tissue injury. However, further mechanistic studies and clinical validation are required for its effective translation into oncologic practice.