Commentary: Indirect action pattern: A remote and cross-organ pharmacological mechanism for drug innovation

The research and development (R&D) of innovative drugs is limited by the low success rates and high attrition of drug candidates, representing an unmet demand for healthy life. A methodological breakthrough of new drug R&D may breed acceleration. In the current issue, Clemens et al. reported a novel indirect action pattern of phosphatidic acid (PA) in an acetaminophen (APAP)-induced liver toxicity model. In this model, PA acted on a remote tissue – epididymal white adipose tissue (eWAT) firstly, and then induced eWAT-derived interlukin-6 as intermediate substance (IMS) to protect against APAP-induced liver injury, while had no effect on the primary disease site–liver. Of note, several recent studies also suggested that besides the conventional methodology of directly targeting the disease primary organ/site, utilizing endogenous substances (e.g., cytokines, microRNA, functional metabolites, or hormones) as IMS to achieve therapeutic purpose should also be considered during new drugs R&D, which we call it indirect action (INDA) here. Taking together, a fundamental breakthrough may be achieved when exploring the new drug R&D methodology from the perspective of INDA, indicating a potential strategy for drug innovation.