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<p>Hyperhomocysteinemia (HHcy) is increasingly recognized as a systemic metabolic disturbance with implications extending beyond a simple biochemical abnormality. Elevated homocysteine levels are associated with multiple organ dysfunctions, yet their integrative mechanistic role remains incompletely defined. To synthesize current evidence on HHcy as a bidirectional metabolic amplifier, integrating epigenetic, oxidative, and vascular mechanisms across organ systems, and to evaluate its translational and clinical implications. A narrative review was conducted using literature from major biomedical databases, focusing on studies published between 2000 and 2025. Key domains included one-carbon metabolism, epigenetic regulation, oxidative stress, vascular dysfunction, and multi-organ disease associations. HHcy disrupts one-carbon metabolism by altering the S-adenosylmethionine/S-adenosylhomocysteine (SAM:SAH) ratio, impairing methylation capacity. This leads to global DNA hypomethylation, histone modifications, and altered gene expression. Concurrently, HHcy promotes mitochondrial dysfunction and reactive oxygen species generation, triggering oxidative stress and activation of inflammatory pathways such as NF-κB and NLRP3. These processes converge to induce endothelial dysfunction, reduced nitric oxide bioavailability, and vascular injury. Clinically, HHcy is associated with cardiovascular disease, neurodegeneration, chronic kidney disease, metabolic liver disease, reproductive dysfunction, and cancer progression. However, homocysteine-lowering interventions have demonstrated inconsistent clinical outcomes, highlighting the influence of genetic variability, baseline homocysteine levels, and organ-specific susceptibility. HHcy functions as a systemic metabolic–inflammatory amplifier linking epigenetic dysregulation, oxidative stress, and vascular pathology. Future strategies should emphasize precision-based interventions, including genotype-guided therapy and risk stratification, to effectively target HHcy and mitigate multi-organ disease progression.</p> Graphical Abstract <p></p>

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Beyond a Biomarker: Hyperhomocysteinemia as a Metabolic-Inflammatory Amplifier and Pharmacological Target in Multisystem Disease

  • 期刊论文

  • 发表日期：

    2026年6月16日

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  • Arush Sharma,
  • Swati Rana,
  • Nishant Goutam,
  • Simran Rana,
  • Shiv Kumar Kushawaha,
  • Mahendra Singh Ashawat

摘要

Hyperhomocysteinemia (HHcy) is increasingly recognized as a systemic metabolic disturbance with implications extending beyond a simple biochemical abnormality. Elevated homocysteine levels are associated with multiple organ dysfunctions, yet their integrative mechanistic role remains incompletely defined. To synthesize current evidence on HHcy as a bidirectional metabolic amplifier, integrating epigenetic, oxidative, and vascular mechanisms across organ systems, and to evaluate its translational and clinical implications. A narrative review was conducted using literature from major biomedical databases, focusing on studies published between 2000 and 2025. Key domains included one-carbon metabolism, epigenetic regulation, oxidative stress, vascular dysfunction, and multi-organ disease associations. HHcy disrupts one-carbon metabolism by altering the S-adenosylmethionine/S-adenosylhomocysteine (SAM:SAH) ratio, impairing methylation capacity. This leads to global DNA hypomethylation, histone modifications, and altered gene expression. Concurrently, HHcy promotes mitochondrial dysfunction and reactive oxygen species generation, triggering oxidative stress and activation of inflammatory pathways such as NF-κB and NLRP3. These processes converge to induce endothelial dysfunction, reduced nitric oxide bioavailability, and vascular injury. Clinically, HHcy is associated with cardiovascular disease, neurodegeneration, chronic kidney disease, metabolic liver disease, reproductive dysfunction, and cancer progression. However, homocysteine-lowering interventions have demonstrated inconsistent clinical outcomes, highlighting the influence of genetic variability, baseline homocysteine levels, and organ-specific susceptibility. HHcy functions as a systemic metabolic–inflammatory amplifier linking epigenetic dysregulation, oxidative stress, and vascular pathology. Future strategies should emphasize precision-based interventions, including genotype-guided therapy and risk stratification, to effectively target HHcy and mitigate multi-organ disease progression.

Graphical Abstract