AI-driven drug discovery targeting cardiac fibrosis in aging heart

The National Institute on Aging (NIA) awarded The Leland Stanford Junior University a $900,195 Cooperative Agreement effective September 1, 2025, through August 31, 2027, under the Aging Research program (CFDA 93.866) to conduct AI-driven drug discovery research targeting cardiac fibrosis in aging populations. Stanford will execute a phased UG3/UH3 study designed to identify and validate novel antifibrotic compounds addressing an unmet clinical need, as no FDA-approved therapies currently exist for cardiac fibrosis—a hallmark of aging that leads to tissue stiffness, impaired cardiac function, and heart failure in elderly populations.

The research deliverables encompass two primary phases. During the UG3 phase, Stanford will perform high-throughput screening of over 225,000 compounds using induced pluripotent stem cell (iPSC)-derived cardiac fibroblast reporter lines and apply the ADMET-AI platform to filter candidates for favorable drug-like properties and low toxicity. In the subsequent UH3 phase, selected compounds will undergo comprehensive in vitro and in vivo validation through testing in "cell villages" for population-scale evaluations and three-dimensional cardiac organoids to assess efficacy and safety. The top two candidate compounds—including a repurposed drug and a novel compound—will be tested in aging mice models to evaluate therapeutic potential in restoring cardiac function and reducing fibrosis. This multidisciplinary approach integrates fibrosis research, artificial intelligence/machine learning tools, and iPSC technology to advance antifibrotic therapy development with potential for clinical translation.

Abstract

Cardiac fibrosis, a hallmark of aging, leads to tissue stiffness, impaired cardiac function, and heart failure, significantly reducing quality of life in elderly populations. Despite its clinical burden, no FDA-approved therapies exist for treating cardiac fibrosis, underscoring an urgent need for innovative solutions. This UG3/UH3 study aims to discover and validate novel antifibrotic compounds by leveraging cutting-edge technologies, including human induced pluripotent stem cells (ipscs), artificial intelligence (AI), and advanced preclinical models. The UG3 phase will focus on high-throughput screening (HTS) of over 225,000 compounds using ipsc-derived cardiac fibroblast (ipsc-CF) reporter lines to identify lead candidates. The admet-AI platform will filter these candidates for favorable drug-like properties and low toxicity. In the UH3 phase, selected compounds will undergo robust in vitro and in vivo validation. This includes testing in "cell villages" for population-scale evaluations and 3D cardiac organoids to assess efficacy and safety in tissue-like environments. The top two hits, including a repurposed drug and a novel compound, will be tested in aging mice to examine their therapeutic potential in restoring cardiac function and reducing fibrosis. This multidisciplinary approach integrates fibrosis research, AI/ML tools, and ipsc technology to address a critical unmet need in aging cardiovascular health. By targeting senescent fibroblasts and employing innovative drug screening platforms, this UG3/UH3 study has the potential to advance the discovery of effective antifibrotic therapies, paving the way for clinical translation and improving outcomes in aging populations.