Small-molecule Inducers of Klotho Expression: Mechanisms, Therapeutic Potential, and Translational Challenges

The anti-aging gene Klotho encodes a multifunctional protein that regulates mineral metabolism, oxidative stress, and cellular homeostasis.Declining Klotho expression is closely associated with aging-related disorders, including chronic kidney disease, cardiovascular dysfunction, and neurodegeneration, making Klotho upregulation an attractive therapeutic strategy.Initial approaches based on recombinant Klotho protein supplementation were limited by inadequate post-translational modifications and reduced biological activity.More recently, adeno-associated virus (AAV)-mediated gene therapy has enabled sustained endogenous Klotho expression; however, concerns regarding dose control, tissue specificity, and long-term safety remain significant barriers to clinical translation.In this context, small-molecule Klotho inducers have emerged as promising alternative therapeutic agents.These compounds enhance endogenous Klotho production while offering advantages in oral bioavailability, manufacturability, and cost-effectiveness.This review systematically evaluates the current landscape of small-molecule Klotho inducers, classifying them according to their mechanistic targets, including epigenetic modulators, transcription factor regulators, signaling pathway inhibitors, oxidative stress modulators, renin-angiotensin system blockers, and synthetic compounds identified through library screening.Preclinical and clinical evidence has demonstrated that Klotho expression can be modulated through diverse regulatory mechanisms involving chromatin remodeling, transcriptional activation, suppression of pro-aging signaling pathways, and redox homeostasis.Despite encouraging progress, key challenges persist, including limited specificity, off-target effects, pharmacokinetic constraints, inter-individual variability, and uncertainty regarding their long-term safety.Addressing these issues will require integrated strategies combining experimental pharmacology, computational modeling, and systems biology.Overall, small-molecule Klotho inducers represent a versatile and clinically viable approach for targeting aging-related and degenerative diseases.This review presents the first integrative, mechanism-based classification of small-molecule Klotho inducers, highlighting key translational challenges and opportunities for their clinical development.