Apoptotic signatures allow early and rapid screening of drug-induced liver injury to accelerate drug discovery.

BACKGROUND: Early detection of drug-induced liver injury (DILI) during drug development is crucial for reducing drug attrition and ensuring the safety of patients. A versatile, biologically interpretable, and dose-dependent screening approach is therefore needed to inform early stop/go decisions and therapeutic margins. METHODS: We have developed AEGIS (Apoptotic Effector Genes In Safety), a preclinical DILI risk screening and prioritization tool that quantifies dose dependent perturbation of apoptosis-regulating transcription factors from transcriptomics data. We profiled transcriptomic responses after short exposures across primary human hepatocytes (PHH), HepG2/C3A cells, RAW 264.7 cells, and an acute Balb/c mouse study. From these profiles, AEGIS provides quantitative risk scores to rank and prioritize compounds and exposures. RESULTS: Here we show that AEGIS distinguishes compounds with different degree of DILI concern, achieving 86% specificity, 75% sensitivity and 90% precision in PHHs. We demonstrate versatility in data type usage and clinical translation of AEGIS with accurate predictions across species, in vitro and in vivo models, and therapeutic modalities. In addition, we apply AEGIS in a precision medicine context during drug-development within the pharmaceutical industry and investigate the contribution of underlying liver disease on DILI severity. Our findings indicate that cells from patients with metabolic dysfunction-associated steatotic liver disease (MASLD) develop more severe DILI from treatment with troglitazone, aligning with preclinical observations. CONCLUSIONS: Using AEGIS early in drug discovery exemplifies a more efficient approach to identify and mitigate potential safety concerns. This can reduce the need for animal testing, and accelerates drug discovery, ultimately providing the right medicines to patients more quickly.