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DOE OSTI · 3008945

A deep generative model for deciphering cellular dynamics and in silico drug discovery in complex diseases

Zheng, Yumin [McGill Univ., Montreal, QC (Canada)] (ORCID:0009000845805247)·Schupp, Jonas C. [Yale Univ., New Haven, CT (United States); Hannover Medical School (MHH) (Germany)] (ORCID:0000000277148076)·Adams, Taylor [Yale Univ., New Haven, CT (United States)] (ORCID:0000000342809070)·Clair, Geremy [Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)] (ORCID:0000000304788520)·Justet, Aurelien [Yale Univ., New Haven, CT (United States)]·Ahangari, Farida [Yale Univ., New Haven, CT (United States)]·Yan, Xiting [Yale Univ., New Haven, CT (United States)]·Hansen, Paul [McGill Univ., Montreal, QC (Canada)]·Carlon, Marianne [Katholieke Univ. Leuven, Heverlee (Belgium)] (ORCID:0000000282630350)·Cortesi, Emanuela [Katholieke Univ. Leuven, Heverlee (Belgium)]·Vermant, Marie [Katholieke Univ. Leuven, Heverlee (Belgium)] (ORCID:0000000185468638)·Vos, Robin [Katholieke Univ. Leuven, Heverlee (Belgium)]·De Sadeleer, Laurens J. [Katholieke Univ. Leuven, Heverlee (Belgium)]·Rosas, Ivan O. [Baylor College of Medicine (BCM), Houston, TX (United States)]·Pineda, Ricardo [Univ. of Pittsburgh, PA (United States)]·Sembrat, John [Univ. of Pittsburgh, PA (United States)]·Königshoff, Melanie [Univ. of Pittsburgh, PA (United States)] (ORCID:0000000194145128)·McDonough, John E. [Yale Univ., New Haven, CT (United States)]·Vanaudenaerde, Bart M. [Katholieke Univ. Leuven, Heverlee (Belgium)] (ORCID:0000000164356901)·Wuyts, Wim A. [Katholieke Univ. Leuven, Heverlee (Belgium)]·Kaminski, Naftali [Yale Univ., New Haven, CT (United States)] (ORCID:0000000159174601)·Ding, Jun [McGill Univ., Montreal, QC (Canada); Mila - Quebec AI Institute, Montreal, QC (Canada)] (ORCID:0000000151836885)
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Abstract

Human diseases are characterized by intricate cellular dynamics. Single-cell transcriptomics provides critical insights, yet a persistent gap remains in computational tools for detailed disease progression analysis and targeted in silico drug interventions. Here we introduce UNAGI, a deep generative neural network tailored to analyse time-series single-cell transcriptomic data. This tool captures the complex cellular dynamics underlying disease progression, enhancing drug perturbation modelling and screening. When applied to a dataset from patients with idiopathic pulmonary fibrosis, UNAGI learns disease-informed cell embeddings that sharpen our understanding of disease progression, leading to the identification of potential therapeutic drug candidates. Validation using proteomics reveals the accuracy of UNAGI’s cellular dynamics analysis, and the use of the fibrotic cocktail-treated human precision-cut lung slices confirms UNAGI’s predictions that nifedipine, an antihypertensive drug, may have anti-fibrotic effects on human tissues. UNAGI’s versatility extends to other diseases, including COVID, demonstrating adaptability and confirming its broader applicability in decoding complex cellular dynamics beyond idiopathic pulmonary fibrosis, amplifying its use in the quest for therapeutic solutions across diverse pathological landscapes.

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Zheng, Yumin [McGill Univ., Montreal, QC (Canada)] (ORCID:0009000845805247), Schupp, Jonas C. [Yale Univ., New Haven, CT (United States); Hannover Medical School (MHH) (Germany)] (ORCID:0000000277148076), Adams, Taylor [Yale Univ., New Haven, CT (United States)] (ORCID:0000000342809070), Clair, Geremy [Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)] (ORCID:0000000304788520), Justet, Aurelien [Yale Univ., New Haven, CT (United States)], Ahangari, Farida [Yale Univ., New Haven, CT (United States)], Yan, Xiting [Yale Univ., New Haven, CT (United States)], Hansen, Paul [McGill Univ., Montreal, QC (Canada)], Carlon, Marianne [Katholieke Univ. Leuven, Heverlee (Belgium)] (ORCID:0000000282630350), Cortesi, Emanuela [Katholieke Univ. Leuven, Heverlee (Belgium)], Vermant, Marie [Katholieke Univ. Leuven, Heverlee (Belgium)] (ORCID:0000000185468638), Vos, Robin [Katholieke Univ. Leuven, Heverlee (Belgium)], De Sadeleer, Laurens J. [Katholieke Univ. Leuven, Heverlee (Belgium)], Rosas, Ivan O. [Baylor College of Medicine (BCM), Houston, TX (United States)], Pineda, Ricardo [Univ. of Pittsburgh, PA (United States)], Sembrat, John [Univ. of Pittsburgh, PA (United States)], Königshoff, Melanie [Univ. of Pittsburgh, PA (United States)] (ORCID:0000000194145128), McDonough, John E. [Yale Univ., New Haven, CT (United States)], Vanaudenaerde, Bart M. [Katholieke Univ. Leuven, Heverlee (Belgium)] (ORCID:0000000164356901), Wuyts, Wim A. [Katholieke Univ. Leuven, Heverlee (Belgium)], Kaminski, Naftali [Yale Univ., New Haven, CT (United States)] (ORCID:0000000159174601), Ding, Jun [McGill Univ., Montreal, QC (Canada); Mila - Quebec AI Institute, Montreal, QC (Canada)] (ORCID:0000000151836885). 2025-06-20. A deep generative model for deciphering cellular dynamics and in silico drug discovery in complex diseases. https://doi.org/10.1038/s41551-025-01423-7

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