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<p>The aldehyde dehydrogenase (ALDH) superfamily plays a critical role in acetaldehyde detoxification. The mitochondrial ALDH2 isoenzyme serves as the core enzyme in alcohol metabolism because of its high affinity for acetaldehyde. Loss-of-function mutation (such as ALDH2*2) of the gene is highly prevalent in East Asian populations. These mutations cause acetaldehyde accumulation and significantly increase the risk of alcohol-related diseases. Therefore, it is necessary to develop efficient recombinant ALDH2 supplementation therapies. However, its heterologous expression faces three major bottlenecks: (1) catalytic turnover leading to NAD⁺ depletion; (2) difficulty in functional tetramer assembly; and (3) cytotoxicity of the substrate acetaldehyde, which inhibits cell growth. The review covers rational host selection and multi-level synergistic optimization of transcription, translation, folding, and metabolism. Examples include promoter optimization, codon optimization, terminator optimization, and chaperone co-expression. Ultimately, we explore essential stabilization formulations and innovative delivery strategies, such as nano-encapsulation and engineered probiotics, needed to realize the therapeutic potential of ALDH2. The goal is to promote the industrial production and clinical translation of recombinant ALDH2.</p>

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Challenges, optimization, and delivery strategies in the heterologous expression of aldehyde dehydrogenase: therapeutic applications for acetaldehyde detoxification

  • 期刊论文

  • 发表日期：

    2026年3月15日

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  • Siyue Qiao,
  • Shumei Li,
  • Tongzheng Zhang,
  • Fan Yang,
  • Rui Ling Zhang,
  • Min Li

摘要

The aldehyde dehydrogenase (ALDH) superfamily plays a critical role in acetaldehyde detoxification. The mitochondrial ALDH2 isoenzyme serves as the core enzyme in alcohol metabolism because of its high affinity for acetaldehyde. Loss-of-function mutation (such as ALDH2*2) of the gene is highly prevalent in East Asian populations. These mutations cause acetaldehyde accumulation and significantly increase the risk of alcohol-related diseases. Therefore, it is necessary to develop efficient recombinant ALDH2 supplementation therapies. However, its heterologous expression faces three major bottlenecks: (1) catalytic turnover leading to NAD⁺ depletion; (2) difficulty in functional tetramer assembly; and (3) cytotoxicity of the substrate acetaldehyde, which inhibits cell growth. The review covers rational host selection and multi-level synergistic optimization of transcription, translation, folding, and metabolism. Examples include promoter optimization, codon optimization, terminator optimization, and chaperone co-expression. Ultimately, we explore essential stabilization formulations and innovative delivery strategies, such as nano-encapsulation and engineered probiotics, needed to realize the therapeutic potential of ALDH2. The goal is to promote the industrial production and clinical translation of recombinant ALDH2.