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Few-shot Learning-driven discovery of Lutein suppresses Th1-mediated inflammation via glucose metabolism

ABSTRACT: Artificial intelligence (AI)-driven drug discovery is often hindered by the “few-shot” data bottleneck and the limited representational power of traditional two-dimensional models, challenging the accurate identification of functional molecules. In this study, we addressed these challenges by establishing a high-precision screening platform, which leverages transfer learning to recognize the key 3D molecular features of T cell inhibitors. Using this approach, we identified Lutein as a novel, specific immunomodulatory agent from a natural product library. Integrated multi-omics analyses revealed that Lutein activates peroxisome proliferator-activated receptor gamma (PPARγ), suppressing glucose uptake and glycolysis, thereby selectively inhibiting Th1 cell differentiation. In a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis, Lutein treatment significantly restored Th1-mediated immune balance and alleviated pathological tissue damage. Our findings not only highlight the great potential of “few-shot” AI strategies that leverage transfer learning and 3D molecular features for the discovery of bioactive natural compounds, but also identify Lutein as a promising therapeutic candidate for ulcerative colitis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE304676 | GEO | 2026/08/03

REPOSITORIES: GEO

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Project description:Carotenoids are essential pigments in photosynthesis and other physiological processes, present in various organisms. Microalgae are considered an important natural source for the commercial production of some of these compounds. The accumulation of the carotenoids astaxanthin and lutein in response to nitrogen and light availability has been optimized in continuous photoautotrophic cultures of Chromochloris zofingiensis. Astaxanthin cellular content increased significantly as the nitrate concentration in the feed medium decreased, while that of lutein remained largely unchanged. The cellular levels of lutein and astaxanthin were inversely correlated with the nitrogen content of the biomass. Thus, for 4% N in the dry biomass, accumulation of astaxanthin was highest and that of lutein lowest. The opposite was recorded for 9% N. Average irradiance positively affected lutein accumulation at both high and low nitrate, whereas that of astaxanthin did only increase under nitrogen-limiting conditions. An integrated analysis of transcriptomics and carotenoid profiling data provides evidence that the response to nitrogen is more significant than that to light availability, and that a synergy exists between both factors, with enhancement of their individual effects. Regulation appears to be orchestrated at several levels: the expression pattern of cyclases suggests a redirection of lycopene to β-carotene, which is converted into astaxanthin through overexpression of BKT1. In turn, slightly higher lutein values are achieved by altering the α-carotene/lutein ratio, due to upregulation of CYP97A1 and CYP97C, especially under high irradiance conditions. The differential responses of astaxanthin and lutein to nitrogen and light availability could enable the programmed generation of C. zofingiensis biomass in continuous culture with a specific astaxanthin to lutein ratio, through careful adjustment of the nitrate concentration in the feed medium, using light irradiance as a modulator.

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Few-shot Learning-driven discovery of Lutein suppresses Th1-mediated inflammation via glucose metabolism

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