Acute kidney injury (AKI) is a life‑threatening condition with limited preventive medications. While the transcription factor Krüppel-like factor 4 (KLF4) is critical to AKI pathophysiology, its underlying molecular mechanisms remain incompletely understood. This study investigates KLF4 from a metabolic perspective and explores the renoprotective potential of doxycycline, an FDA-approved antibiotic. In murine models of ischemia‑reperfusion (IR)‑ and cisplatin (CDDP)‑induced AKI, doxycycline administered significantly attenuated kidney injury and protected renal tubular cells from glucose deprivation- and oxygen‑glucose deprivation-induced stress in vitro. Integrative transcriptomic and metabolomic profiling revealed that AKI progression involves profound metabolic dysfunction, characterized by the downregulation of peroxisomal Acyl-CoA oxidase 3 (ACOX3) and mitochondrial Isocitrate dehydrogenase 2 (IDH2). We identified KLF4 as a dual transcriptional repressor of ACOX3 and IDH2. Mechanistically, molecular docking, surface plasmon resonance, and co-immunoprecipitation assays demonstrated that doxycycline directly binds KLF4 and promotes its ubiquitin-mediated degradation via the E3 ligase FBXO32, which restores ACOX3/IDH2-mediated fatty acid oxidation and the TCA cycle, enhancing cellular resilience against ischemic crisis. These findings define a novel KLF4‑ACOX3/IDH2 metabolic axis and highlight doxycycline as a promising repositioning candidate for AKI prevention.
Ji Feng, Zhiyuan Yao, Yu-hong Li et al.· Pharmacological Research· 0 citations
BACKGROUND
Liver cancer remains the leading cause of cancer-related mortality worldwide, highlighting the need for novel therapeutics. Medicarpin is a pterocarpan, an isoflavonoid derivative, isolated from Spatholobus suberectus Dunn, exhibiting diverse bioactivities, yet its anticancer potential in liver cancer and underlying mechanisms are not well characterized.
PURPOSE
This study aims to investigate the therapeutic efficacy of medicarpin against liver cancer and to elucidate its molecular mechanisms, focusing on its interplay with the epidermal growth factor receptor (EGFR)/signal transducer and activator of transcription 3 (STAT3) signaling and autophagy regulation.
METHODS
A series of in vitro and in vivo assays were conducted to assess medicarpin's effects on apoptosis, EGFR stability, STAT3 signaling and autophagy in liver cancer cells. Molecular docking, cellular thermal shift assay, and drug affinity responsive target stability were employed to confirm target engagement. In vivo efficacy was evaluated using HepG2 xenograft models.
RESULTS
Medicarpin selectively induced apoptosis in liver cancer cells while sparing normal hepatocytes. This effect was independent of p53 status and was mediated through upregulation and membrane accumulation of Fas (Fas cell surface death receptor). Mechanistically, medicarpin directly bound to EGFR, promoted its ubiquitin-mediated degradation, and consequently suppressed the EGFR-STAT3 signaling pathway. Furthermore, medicarpin concurrently triggered protective autophagy, and its inhibition synergistically enhanced its cytotoxicity. In xenograft models, medicarpin significantly suppressed tumor growth.
CONCLUSION
Our findings identify medicarpin as a novel EGFR‑modulating natural compound that induces Fas-mediated apoptosis in liver cancer, independent of p53 status. The concomitant induction of protective autophagy presents a rational combinatory strategy to enhance its therapeutic efficacy. This study underscores the translational potential of medicarpin as a promising candidate for phytotherapy-based liver cancer treatment.
Yong-zhuo Li, Chun-ping Huang, Jing Li et al.· Phytomedicine· 0 citations
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