Seawater aspiration remains a major contributor to drowning-associated death and is a well-recognized cause of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). The injury process is largely driven by breakdown of the alveolar-capillary interface, leading to pulmonary edema, inflammation, and impaired gas exchange. However, therapeutic approaches specifically aimed at preserving barrier integrity are still lacking. In the present study, we investigated whether niclosamide exerts protective effects against seawater aspiration-induced lung injury and explored the mechanisms involved. Using a mouse model of intratracheal seawater challenge, we found that niclosamide substantially alleviated pulmonary damage, reflected by diminished alveolar wall thickening, reduced inflammatory cell accumulation, lower pulmonary edema, and improved lung injury indices, including wet-to-dry weight ratios. In parallel, niclosamide markedly decreased the release of pro-inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Transcriptomic analysis identified enrichment of the Ras-related protein 1 (Rap1) signaling pathway following niclosamide treatment. Consistent with these findings, niclosamide restored the reduction in total Rap1 protein abundance induced by seawater exposure. Importantly, Rap1 knockdown attenuated the protective effects of niclosamide on endothelial barrier function, supporting a functional contribution of Rap1 to the endothelial response to niclosamide. Taken together, our findings identify Rap1 as a functional contributor to endothelial barrier stability in seawater aspiration-induced ALI, and indicate that the endothelial protective effects of niclosamide involve, at least in part, preservation of Rap1.

Asthma is a chronic inflammatory airway disease with limited treatments for airway remodeling. Quercetin has anti-inflammatory potential, but whether it acts through the mtDNA-cGAS-STING pathway remains unclear. This study aimed to explore the therapeutic effect of quercetin on asthma in a mouse model and the associated underlying molecular mechanism. Various doses of quercetin were employed to intervene in a mouse model of asthma. Alterations in inflammation-related indicators and mtDNA in bronchoalveolar lavage fluid (BALF), pathological changes in lung tissue, and activation of the cGAS-STING signaling pathway were detected. The STING agonist DMXAA was utilized to verify whether quercetin could enhance the relevant indicators in the mouse asthma model by suppressing the activation of the mtDNA-cGAS-STING signaling pathway. Finally, BEAS-2B cells were treated with TGF-β to mimic the epithelial-mesenchymal transition (EMT) process of asthmatic epithelial cells. Quercetin, a STING overexpression vector and ethidium bromide intervention were used to analyze whether quercetin inhibited the TGF-β-induced EMT process in BEAS-2B cells by suppressing the mtDNA-cGAS-STING signaling pathway. Quercetin treatment effectively mitigated inflammatory infiltration and airway remodeling in a mouse model of asthma, and the therapeutic effect was most pronounced at a high dose. Additionally, quercetin treatment inhibited the activation of the mtDNA-cGAS-STING signaling pathway in asthmatic mice. Treatment with DMXAA reversed the therapeutic effect of quercetin in the mouse model of asthma. At the cellular level, quercetin inhibited TGF-β-induced EMT in BEAS-2B cells by suppressing the mtDNA-cGAS-STING signaling pathway. Thus, quercetin can ameliorate inflammatory infiltration and airway remodeling in a mouse model of asthma, potentially by suppressing the activation of the mtDNA-cGAS-STING signaling pathway.

Obesity-associated cardiac remodelling (OACR) is characterized by metabolic, structural, mitochondrial, oxidative, and molecular alterations that may contribute to progressive cardiac dysfunction. However, the interplay among mitochondrial quality control, ferroptosis, and calcium homeostasis in obesity-associated cardiac injury and remodelling remains incompletely understood. This study investigated whether betulinic acid (BA) attenuates obesity-induced myocardial injury by modulating these interconnected pathways. Male Sprague-Dawley rats were fed a high-fat diet (HFD) for 16 weeks to induce cardiac injury and remodelling and treated with BA (40 mg/kg, orally) for 6 weeks. Cardiac morphology, metabolic parameters, myocardial bioenergetic parameters, oxidative stress, iron homeostasis, and markers associated with mitochondrial quality control, mitochondrial dynamics, ferroptosis, and calcium regulation were assessed using biochemical, histopathological, mRNA, and protein expression analyses. Molecular docking provided hypothesis-generating predictions of potential interactions between BA and selected regulatory proteins. HFD-induced obesity was associated with alterations in mitochondrial quality-control, ferroptosis-associated, and calcium-regulatory signalling markers, including changes in the SERCA2a-CaMKIIδ axis. BA improved metabolic abnormalities, increased myocardial ATP content and the NAD[+]/NADH ratio, and attenuated oxidative injury and iron accumulation. These effects were accompanied by increased PINK1, Parkin, MFN2, GPX4, SLC7A11, and SERCA2a expression and decreased DRP1, ACSL4, and CaMKIIδ expression. BA attenuated OACR, accompanied by changes in mitochondrial quality-control, ferroptosis-associated, and calcium-regulatory proteins. These findings indicate that modulation of these interconnected pathways may contribute to the attenuation of OACR.

Among the skeletal structures of the wrist joint, an articular disc exists between the cartilage of the distal ulna and carpus, whereas the cartilage of the distal radius almost directly contacts the carpus. In this study, articular cartilage tissues from the distal radius were obtained from donors, and scRNA-seq was conducted. This study provides deep insight into the articular cartilage of the distal radius. Five cartilage tissue samples from the distal radius were obtained from 5 donors, and scRNA-seq was conducted. To verify the distribution of each cell type, the samples were subjected to immunohistochemistry. Ultimately, 51,826 cells were analysed, and 11 cell types were annotated, including FC-A, FC-B, MirCs, SpCs, preHTCs, HTC-A, HTC-B, HomCs, ProCs, ImmCs, and RegCs. Cell‒cell interactions and specific TFs for chondrocyte subsets were identified, which indicate that ATF1, IRF3, KDM5B, and SMARCC2 are specific for SpCs, and ETS2, MXI1, CEBPB, and EGR1 were obviously expressed across cell types and samples. The FN1, COMP and CD99 pathways and cell‒cell interaction patterns of the distal radius may be similar to those of the ankle.

Chemoresistance represents a major obstacle to the successful treatment of gastric cancer (GC). This study aimed to investigate whether baicalein can help overcome cisplatin resistance in GC and explore the involvement of the OMA1/OPA1 axis in this effect. Treatment with baicalein significantly increased mitochondrial fission and ROS levels in AGS cells, reducing ATP production and sensitizing GC cells to cisplatin. Intriguingly, treating AGS cells with the combination of baicalein and cisplatin significantly increased OMA1 expression and reduced OPA1 expression. Mechanistically, we identified a signaling axis linking OMA1 to OPA1 and mitochondrial fission in GC. Moreover, OMA1 overexpression in AGS/DDP cells significantly increased mitochondrial fission and ROS levels, decreased the expression of the OPA1 protein and mitochondrial membrane potential (MMP), and reduced ATP production. Consistently, cell viability and cell apoptosis assays showed that OMA1 overexpression enhanced sensitivity to cisplatin in AGS/DDP cells. Taken together, this study indicated that baicalein improved cisplatin resistance in GC through OMA1/OPA1 axis-mediated modulation of mitochondrial dynamics. These findings support the repurposing of baicalein as a potential agent to reverse cisplatin resistance in GC. Furthermore, the results illuminate how OMA1 regulates mitochondrial dynamics and advocate for combining OMA1 overexpression with chemotherapy in GC.

Although traumatic brain injury (TBI), particularly recurrent concussions during adolescence, is strongly associated with post-traumatic hyperactivity, the role of mitochondrial dysfunction in driving this behavioral alteration remains poorly understood and insufficiently characterized. In this context, we investigated the effects of varying frequencies of recurrent concussions on exploratory behavior, hippocampal mitochondrial bioenergetics, and nitrosative stress in adolescent male Swiss mice (32 days old) subjected to a weight-drop model over 10 days and allocated to Control, 4, 7, and 10-concussion groups. Exploratory behavior was assessed using the open field test 24 h post-injury, while hippocampal mitochondrial respiration (high-resolution respirometry) and nitrosative stress markers (3-nitrotyrosine and iNOS) were evaluated 6 days after the final injury. Twenty-four hours after the final injury, behavioral hyperactivity peaked following 7 concussions. While this phenotype was attenuated after 10 recurrent concussions, exploratory alterations (increased proportion of mobile time, greater time spent in the center, and fewer immobile episodes) persisted relative to controls. Respirometry at 6 days post-injury indicated a threshold effect for mitochondrial dysfunction: although 7 concussions compromised maximal electron transfer capacity, basal and phosphorylation states were impaired only after 10 concussions, resulting in a reduction in ATP synthase activity. The severe bioenergetic failure coincided with increased hippocampal protein nitrosylation (3-NT), indicating a progressive metabolic deterioration subsequent to the early behavioral hyperactivity. Our findings suggest that early hyperactivity precedes bioenergetic failure, reflecting the sequential progression of the injury. Thus, this transient behavioral phenotype may serve as a predictive marker for subsequent mitochondrial collapse.

Breast cancer metastasis is driven by metabolic changes and cellular plasticity, particularly epithelial-mesenchymal transition (EMT). Increasing evidence suggests that increased plasticity due to EMT can be used to reprogram malignant cells toward terminal differentiation. This study investigates the therapeutic potential of Ppar-γ agonists in regulating lipid metabolism and transforming breast cancer cells into post-mitotic, adipocyte-like phenotypes. Using the Py2T mouse breast cancer cell model, EMT was induced with TGF-β, followed by treatment of mesenchymal-like cells with a combination of rosiglitazone (Ppar-γ agonist), trametinib (MEK inhibitor), and paclitaxel (conventional chemotherapeutic agent). Adipogenic phenotypic conversion of the cells was assessed by histological staining (Oil Red O), quantitative PCR, and RNA sequencing targeting 180 genes associated with lipid metabolism and signaling. Our findings demonstrate that mesenchymal breast cancer cells retain significant metabolic plasticity and can be successfully directed towards an adipocyte-like lineage. The combination of rosiglitazone and trametinib significantly increased intracellular lipid accumulation and notably elevated adipogenic markers, including Fabp4 and Ppar-γ. Transcriptomic analysis revealed a coordinated metabolic reprogramming process integrating lipid biosynthesis with cellular motility programs (Itgb3-Itgav) and centered around the Fasn-Srebp1 axis. Furthermore, the addition of paclitaxel consistent with its known antiproliferative pharmacological action, did not further enhance lipid accumulation beyond that observed with rosiglitazone and trametinib alone, while the adipocyte-like phenotype was preserved. In conclusion, this study identifies coordinated changes in lipid metabolism-associated genes during EMT and adipogenic reprogramming of Py2T breast cancer cells. These findings are consistent with a dynamic metabolic regulatory network centered on lipid and sterol metabolism and that warrant further mechanistic validation. Furthermore, they suggest that differentiation-based approaches to target metabolic vulnerabilities and suppress cellular plasticity in aggressive breast cancer subtypes may represent a promising therapeutic strategy that merits further investigation.

Stimulator of interferon genes (STING) is critical for antiviral and intracellular antibacterial immune defense and is involved in pulmonary fibrotic diseases. However, the role of STING in regulating autophagy and airway remodeling in asthma remains unclear. An ovalbumin (OVA)-induced mouse model of asthma airway remodeling was established. Expression levels of STING and autophagy-related gene 5 (ATG5) in lung tissues were detected. The effects of STING inhibitor C-176 on autophagy and airway remodeling were evaluated in vivo. In human bronchial epithelial BEAS-2B cells stimulated with interleukin (IL)-13, the relationships among STING, autophagy, and cellular fibrosis were investigated in vitro. In OVA-challenged mice, C-176, chloroquine (CQ), and dexamethasone (DX) reduced airway hyperresponsiveness and eosinophil counts. C-176 and CQ alleviated inflammatory cell infiltration, mucus secretion, and collagen deposition, and suppressed autophagy and fibrosis in airway epithelium. In IL-13-stimulated BEAS-2B cells, C-176, ATG5 inhibition, or PERK pathway inhibition downregulated autophagy and fibrosis‑related markers. STING upregulation in airway epithelial cells promotes autophagy and subsequent airway remodeling in asthma. Inhibition of STING or autophagy attenuates these pathological changes, indicating a potential therapeutic target for asthma.

Vitamin D plays an important role in immune regulation, yet the relationships among vitamin D status, lymphocyte subsets, and triglycerides (TG) remain incompletely understood. This study aimed to evaluate the associations between serum 25-hydroxyvitamin D [25(OH)D] concentrations, lymphocyte count and subsets, and to examine whether TG statistically contributes to these associations through an indirect pathway. A retrospective cross-sectional analysis was performed in 351 male individuals (mean age 50.22 ± 9.36 years) who underwent routine health screenings. Serum 25(OH)D, TG, lymphocyte count, and lymphocyte subsets (CD3+, CD4+, CD8+, B cells, NK cells) were measured. Pearson correlation, restricted cubic spline, and indirect-effect (mediation) analyses were conducted with adjustment for age, season, physical activity, eGFR, and total bilirubin. 25(OH)D was analyzed as a continuous variable. Serum 25(OH)D was negatively correlated with lymphocyte count (r = - 0.188), CD3 + T cells (r = - 0.209), and CD4 + T cells (r = - 0.218) (all p < 0.01). TG levels were positively correlated with these parameters (r = 0.219, 0.234, and 0.237, respectively; all p < 0.01) and negatively correlated with 25(OH)D (r = - 0.298, p < 0.01). Mediation analysis showed statistically significant indirect effects of TG on the associations between 25(OH)D and lymphocyte count (indirect effect - 3.6, 95% CI -6.7 to - 0.9; 25.4% of the total effect) and between 25(OH)D and CD4 + T-cell count (- 2.0, 95% CI -3.7 to - 0.6; 21.9%), alongside smaller but statistically significant direct effects; these cross-sectional estimates are compatible with, but do not establish, a mediating role of TG. In extended models additionally adjusted for body mass index, fasting plasma glucose, HDL-C and LDL-C, these indirect effects were attenuated (lymphocyte count: -2.4, 95% CI -4.9 to - 0.2; CD3 + T-cell count: -1.7, 95% CI -3.8 to - 0.02), and after further adjustment for smoking and alcohol consumption the bootstrap confidence intervals included zero. Triglycerides may statistically contribute to the association between vitamin D status and selected lymphocyte populations, particularly CD4 + T cells; however, these indirect effects were attenuated after adjustment for metabolic covariates and were no longer statistically significant in the most comprehensively adjusted model. Because of the cross-sectional design, these findings are hypothesis-generating and require confirmation in longitudinal and interventional studies before any clinical relevance can be inferred.

Colorectal cancer (CRC), one of the most prevalent and lethal malignancies worldwide, is driven by complex genetic and molecular alterations. In this study, we aimed to identify the functional role of spindle and kinetochore associated complex subunit 1 (SKA1) and uncover its novel mechanism that promotes CRC progression. Bioinformatic TCGA analysis, paired clinical tissue detection and immunohistochemistry confirmed the elevated SKA1 expression in CRC lesions; high SKA1 expression correlates with unfavorable overall survival in CRC patients. Besides, SKA1 overexpression expedited proliferation, accelerated cell cycle G1/S transition, and enhanced migration and invasion, while suppressing apoptosis in CRC cells, which could be reversed by SKA1 silencing. In vivo, SKA1 silencing suppressed tumor growth in a LoVo cell subcutaneous xenograft nude mouse model, whereas SKA1 overexpression accelerated tumor progression in those derived from SW480 cells. Furthermore, ribosomal protein L8 (RPL8) was identified to interact with SKA1 and mediate the tumor-promoting effects. Silencing RPL8 abolished SKA1-driven proliferation and survival advantages, indicating its downstream role. Subsequently, our studies validated that TATA-box binding protein associated factor 1 (TAF1) directly binds to the SKA1 promoter and transcriptionally activates SKA1 expression. Loss of TAF1 attenuated CRC cell proliferation and invasion, whereas SKA1 overexpression rescued these inhibitory effects. Besides, the truncation mutation of the TAF1 N-terminal TAND domain abolished its binding to the SKA1 promoter and eliminated its transactivation capacity. Collectively, our findings define a novel TAF1/SKA1/RPL8 regulatory axis that critically drives CRC progression, highlighting SKA1 as a potential target and providing new insights into the mechanisms underlying CRC development and progression.

Renal cell carcinoma (RCC) exhibits marked intratumoral heterogeneity that contributes to disease progression and therapeutic resistance. Although ROCK2 has been implicated in RCC progression, its role in regulating tumor cell heterogeneity and cell-state plasticity remains poorly understood. Using single-cell RNA sequencing, we identified a ROCK2-associated stress-responsive transcriptional state characterized by inflammatory signaling and enhanced calcium pathway activity. ROCK2 knockdown was associated with a lower representation of this transcriptional state together with proliferative tumor cells, and integration with the TCGA-KIRC cohort supported the presence of this stress-associated transcriptional program in bulk RCC tumors. Mechanistically, ROCK2 depletion reduced intracellular calcium levels, suppressed CALM1 and CREB1 expression, promoted apoptosis, and impaired cell-cycle progression and proliferation. Pharmacological restoration of calcium signaling with Bay K8644, together with CALM1 or CREB1 overexpression, partially rescued these defects, supporting functional interactions among ROCK2, calcium signaling, CALM1, and CREB1. Collectively, our findings identify a ROCK2-associated stress-responsive transcriptional state linked to altered calcium signaling and provide new mechanistic insight into RCC cellular heterogeneity, highlighting the functional relationship between ROCK2 and calcium signaling as a potential therapeutic vulnerability in RCC.

Oral submucous fibrosis (OSF) is an oral potentially malignant disorder strongly associated with the areca nut alkaloids. Although lysyl oxidase-like 2 (LOXL2) is implicated in pathological collagen accumulation and fibrosis, its regulatory role in OSF progression remains unclear. Hematoxylin-eosin, Masson and immunofluorescent staining were performed on rat oral mucosal tissues to assess fibrotic and senescent phenotypes. Senescence of human oral keratinocytes (HOKs) was assessed by senescence-associated β-galactosidase staining, flow cytometry and western blotting. LOXL2 N6-methyladenosine (m6A) methylation levels in tissues and cells were then detected, and methyltransferase-like 3 (METTL3)-LOXL2 interactions were validated using RNA immunoprecipitation and photoactivatable ribonucleoside-enhanced cross-linking and immunoprecipitation assays. LOXL2 mRNA stability was further assessed after actinomycin D treatment. In addition, lactate levels were measured to explore epithelial-fibroblast crosstalk between HOKs and human oral mucosal fibroblasts. Arecoline-treated rats exhibited progressive epithelial thinning and collagen deposition in oral mucosal tissues, accompanied by upregulated expression of fibronectin, collagen type I, α-smooth muscle actin, p21, and p16. Arecoline exposure elevated reactive oxygen species levels and promoted co-localization of the senescence markers p16/p21 with the epithelial marker cytokeratin. LOXL2 was upregulated in arecoline-induced senescence models, and LOXL2 silencing suppressed fibroblast activation by inhibiting HOKs senescence. Mechanistically, METTL3 stabilized LOXL2 mRNA through m6A-dependent interactions. Downregulation of the METTL3/LOXL2 axis reduced lactate secretion from senescent HOKs, thereby attenuating fibroblast activation. Similar findings were observed in OSF rats. The METTL3/LOXL2 axis may mediate lactate secretion from senescent epithelial cells and regulate epithelial-fibroblast crosstalk during OSF pathogenesis. This study reveals a potential mechanism and candidate targets for further evaluation in OSF.

Pregnant women with preeclampsia (PE) exhibit an exacerbated inflammatory immune response. Hyaluronan (HA), a damage-associated molecular pattern (DAMP), is increased in the plasma of women with PE and may differentially modulate immune responses depending on its molecular weight. Forty-five women were investigated, including 20 with PE, 20 normotensive (NT) pregnant women, and 5 healthy non-pregnant (NP) women. Plasma samples were obtained for TNF, IL-10, HA, and soluble CD44 (sCD44) analyses by ELISA. Expression of the CD44 receptor, as well as intracytoplasmic transcription factors T-bet (Th1), RORγt (Th17), Foxp3 (Treg), and NF-κB, and intracellular cytokines TNF, IL-17, and IL-10, was assessed by flow cytometry. Experiments were conducted on peripheral blood mononuclear cells, followed by cell culture with or without LMW-HA or high-molecular-weight HA (HMW-HA). Pregnant women with PE showed elevated plasma concentrations of HA and TNF, while sCD44 and IL-10 levels were lower than in the NT group. The percentage of CD44-expressing cells was higher among lymphocytes expressing T-bet, RORγt, TNF, and IL-17. Cell stimulation with LMW-HA increased T-bet and RORγt and decreased FoxP3 expression in NT women. LMW-HA stimulation induced higher NF-κB p65 expression in cells from the NP group. Conversely, cell stimulation with HMW-HA decreased RORγt, IL-17, and TNF expression, while increasing FoxP3 and IL-10 expression in preeclamptic women. Overall, HA molecular weight differentially modulated inflammatory- and regulatory-associated markers, with HMW-HA favoring a more regulatory profile and shifting the inflammatory state toward a regulatory-associated profile.

Circadian rhythms orchestrate 24-h oscillations in physiology and gene expression in many tissues, including the heart. Disruptions to these rhythms have been linked to increased cardiovascular risk and impaired cellular homeostasis. However, the extent to which circadian disruption influences cardiac responses to environmental stressors such as alcohol, remains poorly understood. Herein, we performed RNA-sequencing and transcriptomic analysis on hearts from C57BL/6 J mice exposed to alcohol for ten weeks and collected at two distinct circadian time points (Zeitgeber Time (ZT)8 and ZT20). Principal component analysis and differential expression profiling revealed robust time-of-day-dependent transcriptional programs induced by alcohol, with significant enrichment of pathways governing mitochondrial quality control, autophagy/mitophagy, ferroptosis, and key signaling nodes (FOXO, MAPK, AMPK, mTOR, HIF, Hippo). To investigate the impact of circadian disruption, we compared alcohol-challenged hearts from circadian disrupted and control mice. Circadian disruption markedly altered transcriptional profiles and pathways associated with cardiomyopathy and insulin resistance, while further amplifying dysregulation of quality control and stress signaling networks. At the cellular level, alcohol exposure reduced autophagosome formation in isolated adult cardiomyocytes and this decrease was exacerbated by circadian disruption. Further, circadian disruption impaired mitochondrial quality control by reducing ATP production, altering mitophagy, and mitochondrial dynamics, resulting in mitochondrial dysfunction. These alterations were accompanied by increased reactive oxygen species (ROS) production and elevated apoptotic cell death compared with either condition alone. Altogether, these findings demonstrate that circadian disruption exacerbates alcohol-induced molecular and cellular cardiac injury by compromising cellular quality control processes, mitochondrial integrity, and cell survival pathways. These findings identify mechanisms that may contribute to increased susceptibility to alcohol-induced cardiac dysfunction and may offer novel approaches to mitigate alcohol-related cardiac injury in shift-workers or individuals with disrupted circadian rhythms.

Chronic pancreatitis is a progressive fibroinflammatory disease in which activated pancreatic stellate cells and extracellular matrix deposition drive irreversible tissue remodeling. Octreotide has anti-secretory and anti-inflammatory properties, but its anti-fibrotic mechanism remains unclear. To determine whether octreotide attenuates DBTC-induced pancreatic fibrosis through suppression of high-mobility group box 1 (HMGB1) and downstream Wnt/β-catenin signaling. Male Sprague-Dawley rats received dibutyltin dichloride (DBTC, 7 mg/kg) to induce chronic pancreatitis and were assigned to seven groups (n = 10/group) comprising untreated controls, DBTC model rats, and DBTC rats treated with octreotide alone or in combination with HMGB1 overexpression, HMGB1 knockdown, a vector control, or pharmacological Wnt/β-catenin activation. Octreotide was administered at 10 µg/kg/day for 21 days. Pancreatic injury, collagen deposition, stellate cell activation, HMGB1 inflammatory signaling, and Wnt/β-catenin activity were assessed by biochemical assays, histology, hydroxyproline measurement, immunofluorescence, Western blotting, qPCR, and ELISA. DBTC caused weight loss, pancreatic atrophy, elevated amylase/lipase, severe collagen accumulation, and marked increases in collagen I, α-smooth muscle actin (α-SMA), HMGB1, TLR4/RAGE, phospho-NF-κB p65, inflammatory cytokines, active/nuclear β-catenin, Wnt1, phospho-GSK3β, Axin2, c-Myc, and Cyclin D1 (all p < 0.0001 vs. Control). Octreotide substantially reversed these changes, halving fibrosis and hydroxyproline content and suppressing HMGB1 translocation/release (all p < 0.0001 vs. Model). HMGB1 overexpression weakened, whereas HMGB1 knockdown mimicked, octreotide-mediated protection. Wnt activation restored β-catenin activity and fibrosis without significantly changing HMGB1 or TLR4/RAGE/NF-κB signaling (all p > 0.15), a pattern consistent with HMGB1 acting upstream of Wnt/β-catenin. Octreotide limits experimental pancreatic fibrosis by suppressing HMGB1-driven inflammation and downstream Wnt/β-catenin activation, identifying the HMGB1-Wnt/β-catenin axis as a promising anti-fibrotic target.