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Objective <p>Ketohexokinase (KHK) is a critical enzyme in the metabolism of fructose, catalyzing the conversion to fructose-1-phosphate. Excessive fructose consumption, which is primarily processed by the high-activity isoform KHK-C, is responsible for the development of metabolic abnormalities, such as obesity, insulin resistance, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). These disorders also exacerbate hormonal abnormalities in polycystic ovarian syndrome (PCOS). This review examines the potential pharmacotherapeutic applications of KHK in the management of metabolic diseases and PCOS.</p> Methods <p>A systematic review of 231 publications from ScienceDirect, Google Scholar, and PubMed (2005–2024) was carried out in accordance with PRISMA guidelines. 42 studies were added following screening on the basis of their applicability to KHK’s role in metabolic dysfunction and PCOS. With a focus on preclinical and clinical evidence, information about the mechanisms, therapeutic targets, and results of KHK inhibition was extracted.</p> Results <p>Minimizing hepatic fat accumulation, enhancing insulin sensitivity, lowering uric acid levels, and thus minimizing fructose-induced oxidative stress by means of inhibition of KHK, especially KHK-C, has shown promise. In animal models, for example, KHK inhibition resulted in a 25–30% increase in insulin sensitivity and a 35% decrease in hepatic lipid content. Reducing hyperinsulinemia and restoring hormonal balance will help PCOS sufferers as well. Safety and preliminary efficacy in metabolic disorders have been shown by preclinical and early clinical trials using KHK inhibitors including PF-068359.</p> Conclusion <p>KHK inhibition presents a potential method for PCOS and metabolic illness management. Long-term safety and efficacy must thus be established by more clinical studies, nevertheless. Customized therapy plans aiming at KHK could improve metabolic and reproductive results in impacted people.</p>

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Pharmacotherapeutic Role of Ketohexokinase in Metabolic Disorders and PCOS: A Systematic Review

  • 期刊论文

  • 发表日期：

    2025年8月30日

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  • Aditya Srivastava,
  • Gautam Saxena,
  • Nakul Mahawar,
  • Bhawna Chhabra,
  • Havagiray Chitme

摘要

Objective

Ketohexokinase (KHK) is a critical enzyme in the metabolism of fructose, catalyzing the conversion to fructose-1-phosphate. Excessive fructose consumption, which is primarily processed by the high-activity isoform KHK-C, is responsible for the development of metabolic abnormalities, such as obesity, insulin resistance, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD). These disorders also exacerbate hormonal abnormalities in polycystic ovarian syndrome (PCOS). This review examines the potential pharmacotherapeutic applications of KHK in the management of metabolic diseases and PCOS.

Methods

A systematic review of 231 publications from ScienceDirect, Google Scholar, and PubMed (2005–2024) was carried out in accordance with PRISMA guidelines. 42 studies were added following screening on the basis of their applicability to KHK’s role in metabolic dysfunction and PCOS. With a focus on preclinical and clinical evidence, information about the mechanisms, therapeutic targets, and results of KHK inhibition was extracted.

Results

Minimizing hepatic fat accumulation, enhancing insulin sensitivity, lowering uric acid levels, and thus minimizing fructose-induced oxidative stress by means of inhibition of KHK, especially KHK-C, has shown promise. In animal models, for example, KHK inhibition resulted in a 25–30% increase in insulin sensitivity and a 35% decrease in hepatic lipid content. Reducing hyperinsulinemia and restoring hormonal balance will help PCOS sufferers as well. Safety and preliminary efficacy in metabolic disorders have been shown by preclinical and early clinical trials using KHK inhibitors including PF-068359.

Conclusion

KHK inhibition presents a potential method for PCOS and metabolic illness management. Long-term safety and efficacy must thus be established by more clinical studies, nevertheless. Customized therapy plans aiming at KHK could improve metabolic and reproductive results in impacted people.