Industrial production of natural low-calorie sweetener neohesperidin dihydrochalcone

Xiaoxi Zhu; Wei Liu; Yuwan Liu; Huanyu Chu; Jian Cheng; Yadi Gao; Jiayu Liu; Xiaotong Shao; Mengheng Xue; Nida Ahmed; Xiaonan Liu; Lili Song; Huifeng Jiang

doi:10.59717/j.xinn-life.2026.100190

The Innovation Life > 2026 Vol. 4 > No. 1 > 100190

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Industrial production of natural low-calorie sweetener neohesperidin dihydrochalcone

1.
Key Laboratory of Engineering Biology for Low-carbon Manufacturing, Tianjin Institute of Industrial Biotechnology, CAS, Tianjin 300308, China
2.
National Center of Technology Innovation for Synthetic Biology, Tianjin 300308, China
3.
Anhui Jinhe Industrial Co., Ltd., Chuzhou 239200, China
4.
National Key Laboratory for Development and Utilization of Forest Food Resources, Zhejiang A & F University, Hangzhou 311300, China
5.
College of Bioengineering and Food Science, Hubei University of Technology, Wuhan 430068, China
6.
Medical Engineering & Engineering Medicine Innovation Center, Hangzhou International Innovation Institute, Beihang University, Hangzhou 311115, China
7.
These authors contributed equally

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Corresponding author: jiang_hf@tib.cas.cn
Received Date: July 15, 2025

Accepted Date: January 05, 2026

Published Online: January 08, 2026

The Innovation Life 4(1), https://doi.org/10.59717/j.xinn-life.2026.100190 | Cite this article

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PUBLIC SUMMARY

PUBLIC SUMMARY
1. Elucidation and construction of neohesperidin biosynthesis pathway in Yarrowia lipolytica.
  
  A biochemical process for producing neohesperidin dihydrochalcone (NHDC) was developed.
  
  This process enables sustainable, high-yield industrial production of the natural low-calorie sweetener NHDC.

ABSTRACT

ABSTRACT

Neohesperidin dihydrochalcone (NHDC), a natural, low-calorie, high-intensity sweetener derived from plants, faces sustainable supply challenges due to its limited natural abundance. Here we developed a biochemical synthetic process for NHDC production at 5000-L bioreactor system. First, a heterologous synthetic pathway for neohesperidin, which is the precursor of NHDC, was constructed in Yarrowia lipolytica through the screening and assembly of candidate genes sourced from 25 species. Through key gene mining, metabolic flux regulation and fermentation optimization, we constructed 106 engineering strains and improved the titers of neohesperidin by 6,481-fold reaching 28.52 g/L. Finally, the precursor neohesperidin was integrated with a chemical conversion system leading to the establishment of an efficient biochemical process for high-yield NHDC production at an industrial scale. Our findings provide a roadmap for sustainable production of high-value flavonoids and their derivatives.
- Neohesperidin /
- Neohesperidin dihydrochalcone /
- Flavonoids /
- Yarrowia lipolytica /
- Glycorel

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REFERENCES

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Zhu X., Liu W., Liu Y., et al. (2026). Industrial production of natural low-calorie sweetener neohesperidin dihydrochalcone. The Innovation Life 4:100190. https://doi.org/10.59717/j.xinn-life.2026.100190

Zhu X., Liu W., Liu Y., et al. (2026). Industrial production of natural low-calorie sweetener neohesperidin dihydrochalcone. The Innovation Life 4:100190. https://doi.org/10.59717/j.xinn-life.2026.100190

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