In situ mapping of HSA reabsorption by a NIR fluorogenic sensor as a practical phenotypic assay for nephroprotective drug discovery_ Fan Yufan

In situ mapping of HSA reabsorption by a NIR fluorogenic sensor 下载

In situ mapping of HSA reabsorption by a NIR fluorogenic sensor as a practical phenotypic assay for nephroprotective drug discovery

Yufan Fan^a^,^b^,¹, Bei Zhao^b,¹, Ya Zhang^c^,¹, Pingjin Xie^d, Lele Liu^b, Xuerui Wang^b, Guanghao Zhu^b, Zhaobin Guo^a,b, Fangyuan Wang^b^,^****, Qiang Jin^a,b^,^***, Jing Hu^a^,^**, Guangbo Ge^b^,^e^,^*

^aDepartment of Nephrology, The Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China^bState Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China^cDepartment of Pharmacy, Jingan District Zhabei Central Hospital, Shanghai, 200070, China^dShenzhen Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China^eSchool of Pharmacy, Yichun University, Yichun, 336000, China

Keywords:

Human serum albumin (HSA)Ligand-based probe designAlbumin endocytosisNephroprotective agents

ABSTRACT

The impaired reabsorption of kidney tubules is a critical early event in drug-induced kidney injury (DIKI), making real-time monitoring of human serum albumin (HSA) endocytosis essential for assessing renal function and screening nephroprotective agents. Inspired by the specific warfarin-HSA interactions, a novel coumarin- derived near-infrared (NIR) fluorogenic sensor, NCBP, was engineered based on a twisted intramolecular charge transfer (TICT) mechanism. Under physiological conditions, NCBP rapidly and stably bound to sub-domain IIA of HSA with 1:1 stoichiometry, triggering a 79-fold fluorescence enhancement at 665 nm. NCBP integrated multiple advantages for detecting HSA, including instantaneous response, high physicochemical stability, ultrahigh sensitivity, and excellent selectivity. Furthermore, NCBP enabled in situ spatiotemporal im-aging of HSA reabsorption in living nephrocytes and renal tissues, which was then used for screening neph-roprotective agents to mitigate cisplatin-induced nephrotoxicity (CINT). Nobiletin (NOB) and 4’,7- dimethoxyisoflavone (DIF) were identified as promising lead compounds capable of restoring renal uptake function and mitigating cisplatin-induced oxidative stress. In CINT mice, both NOB and DIF significantly improved renal function and attenuated tubular injury, confirming their nephroprotective potentials. Collec-tively, a TICT-based NIR sensor was developed for in situ imaging of HSA reabsorption, offering a robust phenotypic platform for spatiotemporal mapping of cellular HSA trafficking and discovering nephroprotective agents.

1.Introductionto its high incidence and poor prognosis. Drug-induced nephrotoxicity is a leading cause of AKI, with the chemotherapeutic agent cisplatin

Acute kidney injury (AKI), characterized by a sudden decline in renal (CDDP) serving as a typical example (Yang et al., 2025). CDDP triggers a function, imposes a heavy burden on healthcare systems worldwide due cascade of intracellular stresses, including DNA damage, mitochondrial

*Corresponding authors. State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.

**Corresponding author. Department of Nephrology, The Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China.***Corresponding author. Department of Nephrology, The Seventh People’s Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200137, China.****Corresponding author.E-mail addresses: wangfangyuan@zcmu.edu.cn(F. Wang), jindicp@163.com(Q. Jin), hujing@shutcm.edu.cn(J. Hu), geguangbo@shutcm.edu.cn(G. Ge). ¹These authors contributed equally to this work.

https://doi.org/10.1016/j.bios.2026.118490

Received 31 December 2025; Received in revised form 31 January 2026; Accepted 4 February 2026