Next-Generation Therapeutics for Kidney Disease: From Novel Small Molecules to Targeted Protein Degradation

Chronic kidney disease (CKD) and acute kidney injury (AKI) represent a massive global health burden, affecting millions worldwide and driving a rising trajectory of morbidity and mortality. While recent pharmacological breakthroughs, such as the deployment of SGLT2 inhibitors and non-steroidal mineralocorticoid receptor antagonists, have significantly improved the standard of care, these therapies primarily slow disease progression rather than halt or reverse it. The multifaceted pathogenesis of renal disease—driven by chronic inflammation, oxidative stress, metabolic reprogramming, and progressive tubulointerstitial fibrosis—demands therapeutic interventions that extend beyond traditional target inhibition. Consequently, there is an urgent unmet clinical need to explore novel pharmacological modalities capable of engaging previously “undruggable” targets and providing genuine disease-modifying benefits.

This Research Topic aims to spotlight the rapid evolution of renal pharmacology, shifting the paradigm from conventional receptor antagonists to next-generation therapeutic platforms. A major focal point of this collection is the emerging field of Targeted Protein Degradation (TPD), including Proteolysis Targeting Chimeras (PROTACs) and molecular glues. By exploiting the cell’s endogenous ubiquitin-proteasome system, TPD offers a revolutionary approach to selectively eliminate disease-causing proteins that drive renal pathology. Alongside TPD, this collection seeks to highlight the discovery and optimization of advanced novel small molecules, including covalent inhibitors, epigenetic modulators, and highly selective allosteric regulators, which offer unprecedented potency against critical renal targets.

Ultimately, our goal is to bridge the gap between early-stage chemical biology and translational renal medicine. By bringing together medicinal chemists, pharmacologists, and nephrologists, this collection will serve as a comprehensive platform to discuss the efficacy, safety, and translatability of these emerging modalities. We aim to catalyze interdisciplinary collaboration and accelerate the development of precision medicines that can alter the trajectory of devastating kidney disorders.

We welcome Original Research, Review, Mini-Review, and Perspective articles covering, but not limited to, the following themes:

• Targeted Protein Degradation: Design, synthesis, and preclinical evaluation of PROTACs, molecular glues, and other degraders applied to models of AKI, CKD, or polycystic kidney disease.

• Novel Small Molecules: Development and mechanistic profiling of innovative small molecules targeting renal inflammation, fibrosis, apoptosis, and metabolic dysfunction.

• Targeted Delivery Systems: Advances in kidney-targeted drug delivery platforms (e.g., functionalized nanoparticles, antibody-drug conjugates) designed to improve the therapeutic window of next-generation agents.

• Pharmacokinetics and Pharmacodynamics (PK/PD): Profiling the ADME properties, target engagement, and safety profiles of novel renal therapeutics.

• Target Validation: Identification and pharmacological validation of novel druggable targets in renal pathophysiology using advanced chemical probes.

• Translational Pharmacology: Studies bridging in vitro mechanistic discoveries with in vivo efficacy in established preclinical models of kidney disease.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Systematic Review
• Technology and Code

Keywords: Kidney Disease, Targeted protein degradation, PROTACs, Novel small molecules, Chronic kidney disease, Acute kidney injury, Renal pharmacology, Targeted drug delivery, Drug discovery, Renal Function

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.