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Engineering Strategies in Microorganisms for the Enhanced Production of Squalene: Advances, Challenges and Opportunities
Open accessAbstract
The triterpene squalene is a natural compound that has demonstrated an extraordinary diversity of uses in pharmaceutical, nutraceutical, and personal care industries. Emboldened by this range of uses, novel applications that can gain profit from the benefits of squalene as an additive or supplement are expanding, resulting in its increasing demand. Ever since its discovery, the primary source has been the deep-sea shark liver, although recent declines in their populations and justified animal conservation and protection regulations have encouraged researchers to identify a novel route for squalene biosynthesis. This renewed scientific interest has profited from immense developments in synthetic biology, which now allows fine-tuning of a wider range of plants, fungi, and microorganisms for improved squalene production. There are numerous naturally squalene producing species and strains; although they generally do not make commercially viable yields as primary shark liver sources can deliver. The recent advances made toward improving squalene output from natural and engineered species have inspired this review. Accordingly, it will cover in-depth knowledge offered by the studies of the natural sources, and various engineering-based strategies that have been used to drive the improvements in the pathways toward large-scale production. The wide uses of squalene are also discussed, including the notable developments in anti-cancer applications and in augmenting influenza vaccines for greater efficacy.
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“Alternatively, improving squalene production through up-regulation of genes that lead to its synthesis or down-regulation of genes for its degradation is possible [60].”
From Key Targets for Improving Algal Biofuel Production (2021) · cites this paper as [60]
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“Currently, the production of squalene from plants, in particular from olive oil, has been established; however, phytosqualene accounts for only half of the world market, which does not compensate for the volume of squalene obtained from sharks and creates the need to develop more cost-effective technologies for its pr…”
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BackgroundInfluentialFatty acids of Pleurotus florida mushroom: Potential molecules for blood glucose control
Madaan, S., Abduljabbar, S. I., & Panda, B. P. (2022) · Food Bioscience · doi:10.1016/j.fbio.2022.101558 · Cited by 6
Valorization of Seafood Processing By‐Products for Bioactive Compounds
Suresh, P. V., Brundha, A. R., Kudre, T. G., & Sandesh, S. (2023) · doi:10.1002/9781394174867.ch10 · Cited by 6
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“The traditional animal source of squalene, derived from deep-sea shark liver oil, has challenges due to potential pathogen contamination, limiting its suitability for human pharmaceuticals [8,9].”
Sveshnikova, N., & Piercey‐Normore, M. D. (2021) · Diversity · doi:10.3390/d13110529 · Cited by 5
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A review on squalene production by engineered yeasts: Current advances and perspectives
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Optimization of Squalene Production by Pseudozyma sp. P4-22
Huang, C., Song, X., Li, J., Cui, Q., Gu, P., & Feng, Y. (2025) · Molecules · doi:10.3390/molecules30071646 · Cited by 4
“However, growing concerns regarding ecological impacts, resource limitations, and sustainability challenges associated with traditional extraction methods have shifted the research focus toward microbial fermentation as a more viable production strategy [17,20].”
Metabolic engineering of yeast for advanced biofuel production
Yadav, I., Rautela, A., Rawat, S., Namdeo, A. K., & Kumar, S. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-95449-5.00011-4 · Cited by 4
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“For example, PhytoSquene ® , derived from amaranth oil ( Amaranthus caudatus ), offers a non-animal-derived squalene that meets strict pharmaceutical quality standards [191].”
Glucose starvation signaling via nucleus-vacuole junction remodeling controls ergosterol synthesis
Fujimoto, S., & Tamura, Y. (2026) · The Journal of Cell Biology · doi:10.1083/jcb.202506071 · Cited by 3
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Suhendra, S., Septianingsih, L., Ariandi, T. R., Husna, M., Laksana, Z. A., Yuniasih, D., & Hutari, A. (2022) · Jurnal Rekayasa Proses · doi:10.22146/jrekpros.72045 · Cited by 3
Useful Bioactive Compounds from Olive Tree By-Products (Leaves, Branches, Fruits)
Abdallah, M., Aoun, R. B., Amor, M. B., Touhami, I., Habibi, M., & Trabelsi, N. (2023) · Sustainable development and biodiversity · doi:10.1007/978-981-19-8774-8_13 · Cited by 3
Zhang, W., Sunami, K., Liu, S., Zhuang, Z., Sakihama, Y., Zhou, D., Suzuki, T., Murai, Y., Hashimoto, M., & Hashidoko, Y. (2023) · Bioscience Biotechnology and Biochemistry · doi:10.1093/bbb/zbad102 · Cited by 3
Singh, M. N., Vimala, Y., Singh, J., & Nagar, L. (2024) · Vegetos · doi:10.1007/s42535-023-00781-4 · Cited by 3
“It is widespread in animal, vegetal as well as in microbial kingdoms (Gohil et al. 2019).”
Starzonek, S., Drozd-Rzoska, A., & Rzoska, S. J. (2021) · Molecules · doi:10.3390/molecules26195811 · Cited by 3
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“Due to ethical and sustainability concerns, there is growing demand for alternative, non-animal production systems ( 55 , 56 ).”
Combinatorial metabolic engineering for overproduction of squalene in Saccharomyces cerevisiae
Liu, W., Liang, Y., Zhang, X., Shi, J., Xu, Z., Lu, Z., & Li, H. (2025) · Systems Microbiology and Biomanufacturing · doi:10.1007/s43393-025-00340-9 · Cited by 2
“Squalene (C 30 H 50 ) is a linear unsaturated triterpene consisting of thirty carbon atoms [ 1 ], serving as a precursor for the biosynthesis of sterols and steroid hormones in vivo [ 2, 3].”
Introduction to Synthetic Biology
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Kalariya, R. N., Pandya, V. H., Gohil, N., Bhattacharjee, G., Singh, V., Rajani, D. P., Rana, S., Bhosale, R. S., & Yadav, J. S. (2024) · ChemistrySelect · doi:10.1002/slct.202400338 · Cited by 2
Squalene Biosynthesis in Engineered Escherichia Coli
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“30 Inaddition,screeningthe key enzymes of MEP and MVA pathways of different species helps optimize the two pathways, and in turn, in fl uences the subsequent production of squalene.”
BackgroundDaily use of a bakuchiol and squalane-containing face serum impacts skin esthetics
Rastogi, R., & Gholap, A. (2023) · Cosmoderma · doi:10.25259/csdm_224_2023 · Cited by 1
From Olive Pomace to Squalane: A Green Chemistry Route Using 2-Methyltetrahydrofuran
Cravotto, C., Bucciol, F., Mazzitelli, J.-B., Petitcolas, E., Fabiano‐Tixier, A., & Tabasso, S. (2025) · ACS Omega · doi:10.1021/acsomega.5c03685 · Cited by 1
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“While the precise mechanism by which SQ-diEG regulates cholesterol metabolism remains unclear, previous reports suggest that squalene can suppress carcinogenesis by inhibiting HMGCR 20,21 .”
Zhang, Z., Li, R., Chen, Q., Mahmood, S., & Yao, S. (2025) · LWT · doi:10.1016/j.lwt.2025.118594 · Cited by 1
Metadata
- Authors
- Gohil, N., Bhattacharjee, G., Khambhati, K., Braddick, D., & Singh, V.
- Affiliations
- Indian Institute of Advanced Research (IN)
- Genopole (France) (FR)
- Corresponding author
- Singh, Vijai
- Venue
- Frontiers in Bioengineering and Biotechnology
- Publisher
- Frontiers Media SA
- Published
- 2019-03-22
- Volume
- 7
- Pages
- 114-114
- ISSN
- 2296-4185 (ISSN-L)
- PMC
- PMC6439483
- OpenAlex
- W2924306915
- Cited by
- 121
- References
- 199
- Citations by year
- 2026: 15 · 2025: 15 · 2024: 20 · 2023: 21 · 2022: 19 · 2021: 15 · 2020: 14 · 2019: 2
- FWCI
- 1.10
- Type
- journal article
- Language
- en
- Update notices
- corrigendum (2019-05-28)
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Bioengineering and Biotechnology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant biochemistry and biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
- Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Microbial Natural Products and Biosynthesis
- Keywords
- squalene, triterpenoids, synthetic biology, influenza vaccine adjuvants, nutraceuticals, pharmaceutical applications, industrial biotechnology
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