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High-content image-based assays have fueled significant discoveries in the life sciences in the past decade (2013-2023), including novel insights into disease etiology, mechanism of action, new therapeutics, and toxicology predictions. Here, we systematically review the substantial methodological advancements and applications of Cell Painting. Advancements include improvements in the Cell Painting protocol, assay adaptations for different types of perturbations and applications, and improved methodologies for feature extraction, quality control, and batch effect correction. Moreover, machine learning methods recently surpassed classical approaches in their ability to extract biologically useful information from Cell Painting images. Cell Painting data have been used alone or in combination with other - omics data to decipher the mechanism of action of a compound, its toxicity profile, and many other biological effects. Overall, key methodological advances have expanded Cell Painting's ability to capture cellular responses to various perturbations. Future advances will likely lie in advancing computational and experimental techniques, developing new publicly available datasets, and integrating them with other high-content data types., Competing Interests: The authors declare the following competing financial interest(s): S. Singh and A.E.C. serve as scientific advisors for companies that use image-based profiling and Cell Painting (A.E.C.: Recursion, SyzOnc, Quiver Bioscience; S. Singh: Waypoint Bio, Dewpoint Therapeutics, DeepCell) and receive honoraria for occasional talks at pharmaceutical and biotechnology companies. J.C.P. and O.S. declare ownership in Phenaros Pharmaceuticals.

Drug-induced cardiotoxicity (DICT) is a major concern in drug development, accounting for 10-14% of postmarket withdrawals. In this study, we explored the capabilities of various chemical and biological data to predict cardiotoxicity, using the recently released Drug-Induced Cardiotoxicity Rank (DICTrank) dataset from the United States FDA. We analyzed a diverse set of data sources, including physicochemical properties, annotated mechanisms of action (MOA), Cell Painting, Gene Expression, and more, to identify indications of cardiotoxicity. We found that such data, including protein targets, especially those related to ion channels (such as hERG), physicochemical properties (such as electrotopological state) as well as peak concentration in plasma offer strong predictive ability as well as valuable insights into DICT. We also found compounds annotated with particular mechanisms of action, such as cyclooxygenase inhibition, could distinguish between most-concern and no-concern DICT compounds. Cell Painting features related to ER stress discern the most-concern cardiotoxic compounds from non-toxic compounds. While models based on physicochemical properties currently provide substantial predictive accuracy (AUCPR = 0.93), this study also underscores the potential benefits of incorporating more comprehensive biological data in future DICT predictive models. With the availability of - omics data in the future, using biological data promises enhanced predictability and delivers deeper mechanistic insights, paving the way for safer therapeutic drug development. All models and data used in this study are publicly released at https://broad.io/DICTrank_Predictor., Competing Interests: Author Declarations S Singh and AEC serve as scientific advisors for companies that use image-based profiling and Cell Painting (AEC: Recursion, SyzOnc, S Singh: Waypoint Bio, Dewpoint Therapeutics) and receive honoraria for occasional talks at pharmaceutical and biotechnology companies. OS declares shares in Phenaros Pharmaceuticals. LGH is an employee at Ignota Labs where CellScape is a proprietary software. All other authors declare no relevant competing interests.