LCN2 x STAT3

Cisplatin (CP) has been used as an effective chemotherapy drug for different types of cancers. Despite its therapeutic benefits, the clinical utility of CP is often hindered by adverse effects, notably acute kidney injury (AKI), which restricts its widespread application. Dihydromyricetin (DHM) is a flavonoid acquired from Ampelopsis grossedentata, exhibiting a range of pharmacological activities. The major objective of this research was to examine the possible molecular mechanism involved in CP-induced AKI and the protective function of DHM.

In this study, the protective function of DHM against CP-induced AKI was assessed in both mice and HK-2 cells. Kidney dysfunction parameters and renal morphology were evaluated to ascertain the extent of protection. Additionally, proteomics techniques were employed to investigate the protective effect of DHM and elucidate the underlying molecular mechanisms involved in mitigating CP-induced AKI. In addition, protein levels of epidermal growth factor receptor (EGFR), p-EGFR, heat shock protein 27 (HSP27), p-HSP27, STAT3, and p-STAT3 in renal tissues were investigated. Furthermore, an EGFR-blocking agent (gefitinib) or si-RNA of HSP27 was used to study the effects of inhibiting EGFR or HSP27 on CP-induced renal injury.

DHM decreased blood urea nitrogen (BUN) and creatinine in serum, alleviated renal morphological injury and downregulated the expression of CP-induced kidney injury molecule-1 and neutrophil gelatinase-related lipocalin. Proteomic data revealed HSP27 as a potential therapeutic target for AKI. DHM treatment resulted in the downregulation of EGFR, HSP27, and STAT3 phosphorylation, ultimately mitigating CP-induced AKI. In addition, the inhibition of EGFR or HSP27 reduced mitochondria-mediated apoptosis and CP-induced cell damage in HK-2 cells.

DHM effectively inhibited CP-induced oxidative stress, inflammation, and mitochondria-mediated apoptosis through the EGFR/HSP27/STAT3 pathway.

Baricitinib (Bar), used in the management of rheumatoid arthritis, is a selective inhibitor of JAK1/JAK2. Studies have shown that it inhibits the intracellular signaling of many proinflammatory cytokines by suppressing STAT3 activation. Increased expression and activity of JAK1/JAK2 and STAT3 are associated with kidney damage. Here, we examined the effects of the JAK1/JAK2 inhibitor baricitinib (Bar) on kidney damage in a sepsis model created with cecal ligation and puncture (CLP) in rats.

Rats were divided into four groups: control, CLP, CLP + Bar 3 mg kg^-1, and CLP + Bar 10 mg kg^-1. The cecum of animals to which CLP was applied was first ligated distally, then punctured with a needle to allow the fecal content to spread into the abdominal cavity. Two different doses of Bar (3 mg kg^-1, 10 mg kg^-1) were applied to the treatment groups. Biochemical examinations were performed on the sera of animals sacrificed 24 h after CLP, while histopathological and immunohistochemical examinations were performed on kidney tissue.

Bar administration reduced the increased levels of BUN, Cr, TNF-α, IL-1β, KIM-1, NGAL and IL-18 in CLP-induced animal serum, and the levels of kidney tissue TLR-4, p-NF-κB, p-IκBα, IL-6, IL-1β, TNF-α, caspase-8, and caspase-3. At the same time, Bar application was observed to improve the damage in kidney tissue in histopathological examinations. These effects were more pronounced in the group administered 10 mg kg^-1 Bar.

In this study, we found that Bar administration in the experimental sepsis model induced by CLP showed protective properties on the kidney by reducing inflammation and apoptosis dose-dependently.

Oral squamous cell carcinoma (OSCC) is an aggressive malignancy frequently characterized by dysregulated epidermal growth factor receptor (EGFR) signaling. Among EGFR mutation, EGFRvIII, an extracellular domain truncated form without exons 2-7, exhibits ligand-independent and constitutive EGFR activation. Although EGFRvIII functions as an oncogene in glioblastoma, its role in OSCC remains unclear. Here, we demonstrate that EGFRvIII is highly prevalent in OSCC, with approximately 70 % of OSCC tumor samples revealing high EGFRvIII expression. EGFRvIII enhances metastatic and proliferative potential, while its knockdown significantly reduces these malignant phenotypes. Beyond its direct oncogenic effects, EGFRvIII actively remodels the tumor microenvironment (TME) by recruiting and activating fibroblasts. In both xenograft models and co-culture systems, OSCC cells expressing EGFRvIII stimulated the expression of fibroblast activation markers-including α-smooth muscle actin (α-SMA), platelet-derived growth factor receptors (PDGFRA/PDGFRB), and collagen-thereby promoting a tumor-supportive stroma. Moreover, RNA sequencing and cytokine array analyses revealed that EGFRvIII induces lipocalin-2 (LCN2) expression and secretion. Elevated LCN2 in the conditioned medium from OSCC-EGFRvIII cells further stimulates fibroblast activation via the STAT3 signaling pathway, as pharmacological inhibition of STAT3 attenuates LCN2-driven fibroblast activation. Furthermore, exposure to environmental carcinogens such as nicotine-derived nitrosamine ketone (NNK) and arecoline enhances EGFRvIII expression and downstream signaling, exacerbating tumor aggressiveness. These findings reveal a positive feedback loop in which EGFRvIII fosters OSCC progression by stimulating LCN2-STAT3-mediated fibroblast activation. Targeting EGFRvIII and its downstream effectors may therefore represent a promising strategy to mitigate OSCC progression and improve therapeutic outcomes.