Speaker
Description
Title:
Targeting LXRα-R305 Covalent Activation for Renal Copper Homeostasis Restoration by Marine Pestaphilone A as an Anti-AKI candidate
Authors:
Jianglian She (1, 2, 3, 4), Yi Chen (1, 2, 3, 4), Tanwei Gu (2), Xi Zhang (2), Huanguo Jiang (2), Wenxun Lan (2), Lan Tang (2, 3), Xuefeng Zhou (1, 3)
Affiliations:
(1) State Key Laboratory of Tropical Oceanography, Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China.
(2) Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
(3) Guangdong-Hong Kong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
(4) University of Chinese Academy of Sciences, Beijing 100049, China.
*Corresponding authors.
E-mail address: Lan Tang (tl405@smu.edu.cn), Xuefeng Zhou (xfzhou@scsio.ac.cn)
Abstract: No first-in-class therapeutics for acute kidney injury (AKI) have gained global regulatory approval. Furthermore, the mechanism by which the copper modulation attenuates AKI remains elusive. Herein, marine-derived pestaphilone A (PPA) was identified via high-content screening (HCS) of a structurally privileged natural products library and was found to be a potent anti-AKI lead targeting copper homeostasis. More importantly, PPA displayed robust drug development potential, underpinned by its desirable pharmacokinetics (43.9% oral bioavailability) and an acceptable safety margin (LD50 70 mg/kg, i.v.). Combining DARTS analysis with probe (PPA-P) co-localization, we found that liver X receptor α (LXRα), which was significantly downregulated in AKI patients, served as the direct binding target of PPA. A chemical proteomics approach was employed to verify that PPA directly induced the covalent modification of Arg305 on LXRα, an event that initiated a distinct signaling cascade. Mechanistically, this activated LXRα transcriptionally regulated the -1653/-1635 bp fragment of the SLC31A1 (solute carrier family 31 member 1) promoter, which elevated effector proteins CCS (copper chaperone for superoxide dismutase 1) and SOD1 (superoxide dismutase 1), and thereby restored copper homeostasis in AKI. Our findings uncover an unreported LXRα–SCL31A1 axis governing copper homeostasis in AKI, and highlight PPA as the promising anti-AKI candidate.
Background: Acute kidney injury (AKI) denotes a sudden deterioration in kidney function, commonly triggered by ischemia, sepsis, or major surgery such as organ transplantation. It represents a frequent and serious complication in hospitalized patients, particularly in critical care settings. Persisting or severe AKI could lead to volume overload, electrolyte disturbances, accumulation of waste products, and might eventually evolve into chronic kidney disease or end stage renal disease, or even elevate the risk of mortality. Management is currently limited to supportive care, which focuses on fluid resuscitation, hemodynamic optimization, and withdrawal of nephrotoxic drugs, with renal replacement therapy reserved for the most severe cases. However, these strategies do not directly address the underlying cellular and molecular mechanisms of kidney injury, nor do they actively promote renal repair. Moreover, the heterogeneity of AKI etiology and the lack of disease-driving targets have hindered the development of targeted therapies. Existing candidates are often limited by insufficient target selectivity and significant off‑target effects. Therefore, despite advances in supportive care, there remains a pressing, unmet need for effective pharmacological interventions preventing or reversing AKI. (Leng et al.: Kidney Int. 103 (2023) 100-114).
Methods: In this study, both in vitro and in vivo models verified that the natural product PPA possessed therapeutic potential for acute kidney injury and served as a promising candidate molecule for further investigation.
Results: The marine-derived natural product PPA was identified through HCS, and in vivo experiments confirmed that it is a potent lead compound targeting copper homeostasis for the treatment of AKI. This compound exhibits an oral bioavailability of 43.9% and an LD50 of 70 mg/kg, demonstrating robust drug development potential and a favorable safety margin.
Conclusions: Collectively, our study identified marine-derived PPA as a promising anti-AKI candidate targeting copper homeostasis, revealed its direct target LXRα and covalent modification at Arg305, uncovered the novel LXRα–SLC31A1 signaling axis responsible for restoring copper homeostasis by regulating CCS and SOD1, and further supported its translational potential with favorable pharmacokinetic and safety profiles.
Acknowledgments:
Supported by the National Natural Science Foundation of China (U24A20809, 82274002, 82473993), National Key Research and Development Program of China (2024YFC2815900), and Guangdong Basic and Applied Basic Research Foundation (2024A1515010741, 2024A1515012477).