Integrating Literature Evidence to Enhance CRISPR-based Target Screening for Hand-foot Syndrome

Abstract

The experimental high-throughput screening (HTS) methods, exemplified by CRISPR- based screening techniques, have revolutionized target identification in drug discovery. However, such screens frequently yield extensive, often unrelated target lists necessitating costly and time-intensive experimental evaluation and validation. To address this challenge, we propose a dual-filter strategy that integrates literature-mined targets with CRISPR/Cas9 screening outputs, systematically prioritizing the most credible candidates and thereby reducing the experimental validation burden and increasing success rate. To validate this strategy, we applied it with hand-foot syndrome (HFS), a clinically challenging side effect induced by fluoropyrimidine treatment. We identified ATF4 as a key regulator of 5-fluorouracil (5-FU) toxicity in the skin and revealed forskolin as a potential therapeutic agent of HFS through the strategy. Mechanistically, forskolin triggers MEK/ERK-dependent ATF4 induction, subsequently driving 5-FU detoxification via the ATF4-mediated eIF2/I{kappa}B signaling pathway. Our findings demonstrate that this dual-filter strategy could notably accelerate drug discovery by reducing experimental validation burden after target screening.