Zhongping Su

Background/Aims: Changes in blood glucose are correlated with metabolic dysfunction associated steatotic liver disease (MASLD). The stress hyperglycemia ratio (SHR) serves as an innovative biomarker for accurately assessing acute hyperglycemia. This investigation aimed to analyze the correlation of SHR with advanced liver fibrosis and mortality among MASLD patients. Materials and Methods: This retrospective analysis enrolled 8078 individuals with MASLD (fatty liver index ≥60) from the National Health and Nutrition Examination Survey 1999-2018. The outcomes were advanced liver fibrosis (fibrosis 4 index >2.67), all-cause mortality (ACM), and cardiovascular disease–related mortality (CRM), and death information was recorded through December 31, 2019. The SHR was calculated using fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) according to the following formula: [FPG (mmol/L) / (1.59 × HbA1c (%) - 2.59)]. Results: Among the 8078 patients, advanced liver fibrosis was identified in 243 (2.12%) patients, while ACM and CRM accounted for 1250 (9.12%) and 421 (2.92%) patients, respectively. High SHR demonstrated a correlation with higher risks of advanced liver fibrosis [odds ratio (OR, 95% CI) = 1.87 (1.15-3.04)] and ACM [hazard ratio (HR, 95% CI) = 1.45 (1.11-1.89)]. Low SHR was also related to a higher risk of ACM [HR = 1.34 (1.00-1.78)]. The SHR showed a U-shaped nonlinear relationship with advanced liver fibrosis, ACM, and CRM, and the lowest SHR values were 0.924, 0.924, and 0.945, respectively. Conclusion: The SHR exhibited a U-shaped relationship with the risk of advanced fibrosis and mortality among MASLD patients. Cite this article as: Su Z, Ling T, Mao R, Yang X, Wang J, Xu Y. Association of the stress hyperglycemia ratio with advanced liver fibrosis and mortality in patients with metabolic dysfunction–associated steatotic liver disease: An analysis of NHANES. Turk J Gastroenterol. Published online February 16, 2026. doi: 10.5152/tjg.2026.25707.

Background: GPR84 is a Gi-coupled G-protein-coupled receptor (GPCR) predominantly expressed in immune cells, with its expression upregulated during inflammatory conditions. However, its specific role in immune-mediated liver injury remains unclear. Methods: We utilized a concanavalin A (Con A)-induced mouse model to simulate immune-mediated liver injury. The expression of GPR84 was assessed by quantitative RT-PCR and western blotting. GPR84 gene knockout mice were employed to evaluate the receptor’s functional role. Bone marrow chimeric mice were created to determine the involvement of hematopoietic cells. Infiltrating liver inflammatory cells were analyzed by flow cytometry. The activation of key signaling pathways in hepatic tissues was assessed by western blotting. The GPR84 antagonist GLPG1205 was tested in this model to evaluate its therapeutic potential. Results: GPR84 expression was significantly upregulated in the mouse liver following Con A injection. Mice lacking GPR84 exhibited reduced serum ALT and AST levels, diminished liver damage, and decreased apoptosis. Additionally, the expression levels of inflammatory cytokines MCP-1 and TNF-α were significantly lower in Gpr84 ^−/− mice compared to wild-type (WT) mice after Con A injection. Flow cytometry analysis revealed a notable reduction in the proportion of Kupffer cells and infiltrating monocytes (CD11b⁺Ly6C^lowLy6G⁻) in Gpr84 ^−/− mice. Using bone marrow chimeric mice, we demonstrated that GPR84-deficient bone marrow-derived cells mitigate Con A-induced liver injury. Furthermore, GPR84 deficiency was associated with reduced hepatic apoptosis and lower phosphorylation levels of STAT3, ERK, JNK, p38, and p65, effectively inhibiting key inflammatory signaling pathways. Importantly, treatment with the GPR84 antagonist GLPG1205 significantly lowered serum ALT and AST levels, reduced the expression of inflammatory cytokines, and alleviated liver damage. Conclusions: Our findings suggest that GPR84 plays a pivotal role in immune-mediated liver injury, primarily through its expression on hematopoietic cells. Targeting GPR84, particularly with the antagonist GLPG1205, offers a promising therapeutic strategy for treating immune-related liver diseases.

Drug-induced liver injury (DILI) still poses a major clinical challenge and is a leading cause of acute liver failure. Inhibitor of nuclear factor kappa B kinase subunit epsilon (IKBKE) is essential for inflammation and metabolic disorders. However, it is unclear how IKBKE regulates cellular damage in acetaminophen (APAP)-induced acute liver injury. Here, we found that the deficiency of IKBKE markedly aggravated APAP-induced acute liver injury by targeting RIPK1. We showed that APAP-treated IKBKE-deficient mice exhibited severer liver injury, worse mitochondrial integrity, and enhanced glutathione depletion than wild-type mice. IKBKE deficiency may directly upregulate the expression of total RIPK1 and the cleaved RIPK1, resulting in sustained JNK activation and increased translocation of RIPK1/JNK to mitochondria. Moreover, deficiency of IKBKE enhanced the expression of pro-inflammatory factors and inflammatory cell infiltration in the liver, especially neutrophils and monocytes. Inhibition of RIPK1 activity by necrostatin-1 significantly reduced APAP-induced liver damage. Thus, we have revealed a negative regulatory function of IKBKE, which acts as an RIPK1/JNK regulator to mediate APAP-induced hepatotoxicity. Targeting IKBKE/RIPK1 may serve as a potential therapeutic strategy for acute or chronic liver injury.

Hepatoblastoma is the most frequent liver malignancy in children. HepG2 has been discovered as a hepatoblastoma-derived cell line and tends to form clumps in culture. Intriguingly, we observed that the addition of calcium ions reduced cell clumping and disassociated HepG2 cells. The calcium signal is in connection with a series of processes critical in the tumorigenesis. Here, we demonstrated that extracellular calcium ions induced morphological changes and enhanced the epithelial-mesenchymal transition in HepG2 cells. Mechanistically, calcium ions promoted HepG2 proliferation and migration by up-regulating the phosphorylation levels of focal adhesion kinase (FAK), protein kinase B, and p38 mitogen-activated protein kinase. The inhibitor of FAK or Ca ²⁺/calmodulin-dependent kinase Ⅱ (CaMKⅡ) reversed the Ca ²⁺-induced effects on HepG2 cells, including cell proliferation and migration, epithelial-mesenchymal transition protein expression levels, and phosphorylation levels of FAK and protein kinase B. Moreover, calcium ions decreased HepG2 cells' sensitivity to cisplatin. Furthermore, we found that the expression levels of FAK and CaMKⅡ were increased in hepatoblastoma. The group with high expression levels of FAK and CaMKⅡ exhibited significantly lower ImmunoScore as well as CD8 ⁺ T and NK cells. The expression of CaMKⅡ was positively correlated with that of PDCD1 and LAG3. Correspondingly, the expression of FAK was negatively correlated with that of TNFSF9, TNFRSF4, and TNFRSF18. Collectively, extracellular calcium accelerates HepG2 cell proliferation and migration via FAK and CaMKⅡ and enhances cisplatin resistance. FAK and CaMKⅡ shape immune cell infiltration and responses in tumor microenvironments, thereby serving as potential targets for hepatoblastoma.

Hypertension is a pathological condition of persistent high blood pressure (BP) of which the underlying neural mechanisms remain obscure. Here, we show that the afferent nerves in perirenal adipose tissue (PRAT) contribute to maintain pathological high BP, without affecting physiological BP. Bilateral PRAT ablation or denervation leads to a long-term reduction of high BP in spontaneous hypertensive rats (SHR), but has no effect on normal BP in control rats. Further, gain- and loss-of-function and neuron transcriptomics studies show that augmented activities and remodeling of L1-L2 dorsal root ganglia neurons are responsible for hypertension in SHR. Moreover, we went on to show that calcitonin gene-related peptide (CGRP) is a key endogenous suppressor of hypertension that is sequestered by pro-hypertensive PRAT in SHRs. Taken together, we identify PRAT afferent nerves as a pro-hypertensive node that sustains high BP via suppressing CGRP, thereby providing a therapeutic target to tackle primary hypertension.

Vascular calcification is an important risk factor for the mortality and morbidity in chronic kidney disease (CKD). Unfortunately, until now there is no certain medication targeting vascular calcification in CKD. In this study, we explored the inhibitory effect of celastrol on high calcium–induced vascular calcification and the underlying molecular mechanisms. Cell proliferation assay showed that celastrol inhibited aortic valve interstitial cell (VIC) and vascular smooth muscle cell (VSMC) proliferation when its concentration was higher than 0.6 μmol/L. 0.8 μmol/L celastrol inhibited the expression of osteogenic genes and calcium deposition induced by high‐calcium medium in both AVICs and VSMCs. In mouse vascular calcification model induced by adenine combined with vitamin D, alizarin red and immunostaining showed that celastrol inhibited pro‐calcification gene expression and calcium deposition in aortic wall and aortic valve tissues. At the molecular level, celastrol inhibited the increase of BMP2, phosphorylated Smad1/5 (p‐Smad1/5) and non‐phosphorylated β‐catenin (n‐p‐β‐catenin) induced by high‐calcium medium both in vitro and in vivo. Also, BMP2 overexpression reversed the anti‐calcification effects of celastrol by recovering the decrease of p‐Smad1/5 and n‐p‐β‐catenin. Furthermore, celastrol prevented the up‐regulation of BMPRII and down‐regulation of Smad6 induced by high calcium, and this protectory effect can be abolished by BMP2 overexpression. In conclusion, our data for the first time demonstrate that celastrol attenuates high calcium–induced arterial and valvular calcification by inhibiting BMP2/Smad1/5 signalling, which may provide a novel therapeutic strategy for arterial and valvular calcification in patients with CKD.

Aberrant increase in angiogenesis contributes to the progression of malignant solid tumors. An alternative anti‑angiogenesis therapy is critical for cancer, since the current anti‑angiogenesis drugs lack specificity for tumor cells. In the present study, the effects and mechanisms of low‑intensity pulsed ultrasound (LIPUS) on human umbilical vein endothelial cells (HUVECs) and human microvascular endothelial cells (HMECs) were investigated, and the therapeutic potential of this technology was assessed. HUVECs and HMECs were treated with LIPUS (0.5 MHz; 210 mW/cm2) for 1 min and cultured for 24 h. Flow cytometry and Cell Counting Kit‑8 assays demonstrated that LIPUS treatment at a dose of 210 mW/cm2 promoted apoptosis and decreased the viability in HUVECs and HMECs. Real‑time cell analysis also revealed that LIPUS did not affect the proliferation or migration of HUVECs. An endothelial cell tube formation assay indicated that LIPUS treatment inhibited the angiogenic ability of HUVECs and HMECs. Furthermore, LIPUS increased the protein levels of the apoptosis‑associated cleaved Caspase‑3 and decreased the B‑cell lymphoma‑2 levels. LIPUS increased the phosphorylation of p38 mitogen‑activated protein kinase (MAPK), and the levels of endoplasmic reticulum (ER) stress‑associated markers, including activating transcription factor‑4 (ATF‑4) and phosphorylated eukaryotic initiation factor 2α (eIF2α). The p38 inhibitor SB203580 reversed the pro‑apoptotic and anti‑angiogenic effects of LIPUS in cells. Finally, inhibition of p38 decreased the LIPUS‑induced elevation of p‑eIF2α and ATF‑4 levels. Taken together, these results suggested that LIPUS promoted apoptosis and inhibited angiogenesis in human endothelial cells via the activation of p38 MAPK‑mediated ER stress signaling.