Injectable glycol chitosan-dexamethasone prodrug thermogel for otoprotective therapy against radiation-induced middle ear injury.

Preclinical studies are valuable tools for screening new drugs, and reports suggest that the administration of glucocorticoids, such as dexamethasone (DEX), can induce neurochemical and behavioral changes linked to depression and memory deficits. The organoselenium compound 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1) has demonstrated antidepressant-like effects and protection against memory impairments in previous studies. The present study investigated the impact of repeated SeBZF1 administration on a subchronic DEX administration protocol in female Swiss mice. The animals received daily intraperitoneal injections of DEX (2mg/kg) or its vehicle for 21 days. In the last 7 days of the protocol, the compound SeBZF1 (1 or 5mg/kg) or its vehicle was administered intragastrically. The 1st set revealed that SeBZF1 attenuated the increase in immobility time in the tail suspension test and the memory decline in the Y-maze test induced by DEX. The 2nd set confirmed the actions of SeBZF1 by the forced swimming test and through the object recognition test. Furthermore, SeBZF1 reduced the reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS) levels induced by DEX administration in the prefrontal cortex and reduced ROS levels in the hippocampus. In addition, treatment with the compound modulated the monoamine oxidase A activity in the hypothalamus and acetylcholinesterase in the hippocampus. In summary, the present study elucidates the promising action of repeated SeBZF1 treatment in an experimental model of subchronic DEX administration in female Swiss mice.

Withanolides from Datura stramonium: two unprecedented B-ring-seco derivatives and anti-inflammatory active analogues.

Microparticle-based drug delivery systems have gained widespread recognition for their ability to enable sustained drug release. However, their utility in oral administration has been constrained by suboptimal gastrointestinal retention. This study systematically evaluated how engineered microparticle morphology and surface topography influence intestinal adhesion dynamics and drug release profiles. Through controlled modulation of surface roughness and particle geometry, we demonstrated that non-spherical architectures, particularly waterdrop-like microparticles (WDMPs), exhibited superior mucoadhesive properties, achieving 1.25-fold prolonged gastrointestinal retention time while maintaining optimal drug release kinetics (71.2% cumulative release over 10 h). In a murine inflammatory bowel disease (IBD) model, dexamethasone (DXM)-loaded WDMPs outperformed conventional free drug administration, manifesting in significantly improved therapeutic outcomes: 1.16-fold enhanced weight recovery, 1.27-fold greater colon length preservation, and superior histopathological scores. Notably, WDMPs also boosted oral bioavailability of micronutrients by 1.2-to-1.6-fold, highlighting its dual applicability for both pharmaceutical and nutraceutical delivery. These comprehensive findings positioned WDMPs as a transformative oral delivery platform that addresses longstanding challenges in gastrointestinal drug absorption, offering substantial potential for clinical translation. STATEMENT OF SIGNIFICANCE: This study demonstrates the potential of engineered microparticle morphology to address key challenges in oral drug delivery. By investigating the effects of particle morphology and surface topography on intestinal retention and drug release, we show that non-spherical, rough microparticles exhibit enhanced mucoadhesion and sustained drug release. Waterdrop-like Microparticles (WDMPs) provide a significant improvement in gastrointestinal retention and drug release kinetics. WDMPs also outperform free dexamethasone in a murine model of inflammatory bowel disease. Additionally, WDMPs enhance oral bioavailability for micronutrients, offering dual-purpose potential for pharmaceutical and nutraceutical applications. These findings highlight the critical role of microparticle morphology in optimizing drug delivery efficiency and underscore the versatility of WDMPs as a customizable platform for controlled release therapies.

Traumatic brain injury (TBI) can induce both primary and secondary brain injuries. Hampered by a multitude of constraints, including the complexity of secondary injury pathophysiological mechanisms, the selective permeability of the blood-brain barrier (BBB), and the side effects of therapeutic agents, systemic monotherapy has demonstrated limited efficacy in improving the long-term prognosis of TBI patients. Therefore, there is an urgent need to develop novel therapeutic strategies that can bypass the BBB, avoid systemic complications, and target multiple secondary injury mechanisms simultaneously. An injectable dual-drug-loaded nanohydrogel system was synthesized and its characteristics were evaluated. A mouse controlled cortical impact (CCI) model was established, and the nanohydrogel was locally administered intraoperatively. The neurological prognosis of mice was observed in both acute and chronic phases. Multiple methods, including evans blue assay, magnetic resonance imaging, transmission electron microscopy, western blot, enzyme-linked immunosorbent assay, and immunofluorescence staining, were used to evaluate the cerebral edema, BBB integrity, neuroinflammation, neuronal death/survival, angiogenesis, and neurogenesis after TBI. The nanohydrogel hybridizes hemoglobin (Hb) nanoparticles (NPs) with brain-derived neurotrophic factor (BDNF), uses these as the core to synthesize polydopamine (PDA) NPs, and loads dexamethasone (DEX) on their surface. In vitro drug release experiments confirmed that BDNF@Hb-PDA@DEX@gel had a high drug-loading rate and sequential sustained-release characteristics. The hydrogel matrix exhibited hemostatic and antibacterial effects. Both in vitro and in vivo experiments showed that the nanohydrogel could effectively reduce the acute-phase inflammatory response, protect BBB integrity, and alleviate cerebral edema by releasing DEX. In the late stage, it could promote brain tissue repair by releasing BDNF, including angiogenesis, neurogenesis, and neuron survival. The therapeutic efficacy of this dual-drug sequential delivery system was significantly superior to that of DEX monotherapy, and it could improve both acute and chronic neurological functions. By virtue of local sequential and sustained release of multiple drugs, the injectable nanohydrogel-based dual-drug delivery system can target multiple secondary injury mechanisms of TBI and exert spatiotemporal therapeutic effects, which provides a new strategy for the effective management of complex secondary brain injury and the improvement of long-term prognosis in TBI.

Targeting microglial dysfunction: The antioxidant potential of and the regulation of microglial responsiveness by dermatan sulfate from a marine invertebrate.

Skeletal muscle adaptation to physiological and pathological stressors requires precise coordination of protein synthesis and mitochondrial function. While the roles of canonical translation regulators such as eIF2α and 4E-BP1 in exercise-induced protein synthesis modulation are well established, the contribution of eIF3, the largest eukaryotic initiation factor complex, to muscle stress responses remains poorly understood. Eukaryotic initiation factor 3 (eIF3) regulates mRNA translation and mitochondrial homeostasis, yet how individual eIF3 subunits respond to distinct modes of skeletal muscle stress remains unclear. Here, we systematically characterized eIF3 dynamics and mitochondrial function using two complementary mouse models: acute exhaustive training and dexamethasone (DEX)-induced atrophy. Integrated proteomic, transcriptional, and imaging analyses revealed a biphasic regulatory pattern: DEX treatment caused broad downregulation of eIF3a, eIF3b, eIF3c, eIF3g, and eIF3l, concurrent with comprehensive mitochondrial electron transport chain (ETC) impairment, while acute training selectively decreased eIF3d, eIF3e, eIF3g, and eIF3l but uniquely preserved eIF3f expression alongside adaptive ETC remodeling. This differential response pattern distinguishes eIF3 from other stress-responsive translation factors, as eIF2α phosphorylation typically causes global translation suppression whereas eIF3 dysregulation selectively impairs mitochondrial protein synthesis. Notably, eIF3f preservation under both conditions suggests a compensatory mechanism to maintain translational capacity. siRNA-mediated knockdown of eIF3e or eIF3f in C2C12 myotubes demonstrated their differential effects on mitochondrial protein expression and atrophy signaling, with eIF3f knockdown causing more severe mitochondrial protein suppression. Seahorse XF analysis confirmed that eIF3 subunit loss directly impairs mitochondrial oxygen consumption, while SUnSET assays demonstrated attenuated global protein synthesis upon eIF3e or eIF3f depletion. Furthermore, eIF3 knockdown suppressed mTORC1 signaling (p-mTOR, p-4EBP1, p-S6K, p-S6) and differentially modulated ubiquitin-proteasome activity without altering bulk autophagy. These findings establish eIF3 as a molecular integrator linking translational control to mitochondrial integrity in skeletal muscle physiology, positioning this complex as a potential therapeutic target for conditions ranging from exercise-induced adaptation to muscle wasting disorders.

Spermidine mitigates glucocorticoid-induced bone osteoporosis by targeting oxidative stress and RANKL/OPG pathway.

Transmucosal drug delivery is an attractive noninvasive strategy, yet its efficiency is fundamentally limited by the trade-off between mucus penetration and mucoadhesion. Here, we present salivary enzyme-responsive penetration-to-adhesion switching nanoparticles (SEPAS NPs) designed to overcome this limitation in the context of buccal drug delivery. SEPAS NPs feature a dual-regime architecture consisting of an N-guanidinium chitosan oligosaccharide (G-COS) inner layer that provides mucoadhesion and a degradable starch-based outer layer that transiently shields cationic interactions with mucins during transport. Under mucus-mimicking conditions, SEPAS NPs exhibit minimal mucin binding during penetration, followed by enzyme-mediated degradation of the starch shell that exposes the underlying G-COS layer and enhances retention at a mucin-coated interface by approximately 6-fold. Furthermore, this switching design does not compromise drug release, maintaining diffusion-dominated sustained release of dexamethasone (DEX). In addition, SEPAS NPs demonstrate excellent cytocompatibility (>90% cell viability) and maintain the anti-inflammatory activity of released DEX. Collectively, this work presents an enzyme-responsive nanoparticle strategy that resolves the penetration-adhesion trade-off while maintaining favorable release kinetics and biocompatibility, providing a broadly adaptable platform for transmucosal drug delivery across diverse mucus environments.

Kv1.3 Modulates Macrophage M2 Polarization via the STAT3 Pathway: A Novel Mechanism and Therapeutic Target for Steroid-Resistant Asthma.

The cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS-STING) pathway mediates anti-tumor immunity by sensing cytosolic DNA and producing type I interferons, but is frequently suppressed in multiple myeloma (MM), enabling immune evasion. Dexamethasone (DXM), a cornerstone glucocorticoid in MM therapy, is paradoxically combined with immunotherapies despite its immunosuppressive reputation. The mechanisms by which DXM and its glucocorticoid receptor (GR) modulate the MM immune microenvironment remain elusive. We analyzed the tumor immune microenvironment using single-cell RNA sequencing in 5TMM3VT murine models. STING-knockout mice were employed for genetic validation, and the PP1 inhibitor salubrinal for pharmacological studies. Protein-protein interactions were examined by co-immunoprecipitation, mass spectrometry, and immunofluorescence. NK cell cytotoxicity and macrophage polarization were assessed using co-culture systems with flow cytometry, quantitative real-time PCR, and ELISA. We identified that GR constitutively recruits the phosphatase PPP1CB to dephosphorylate and inactivate the TBK1-IRF3 complex, thereby suppressing cGAS-STING signaling in MM cells under basal conditions. As the specific ligand of GR, DXM rapidly binds to GR, leading to the disruption of the GR-PPP1CB-TBK1-IRF3 complex, which in turn reactivates STING signaling and induces interferon-stimulated gene expression. Single-cell analysis revealed that DXM remodeled the immune microenvironment, enhancing NK cell cytotoxicity, and promoting M1-like macrophage polarization. These immunostimulatory effects were abrogated in STING-deficient models. Pharmacological inhibition of PP1 with salubrinal recapitulated DXM's effects, synergized with bortezomib to prolong survival in vivo, and enhanced daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). This study uncovers a glucocorticoid-sensitive inhibitory axis wherein GR-PPP1CB constitutively suppresses STING-TBK1-IRF3 signaling in MM. DXM relieves this suppression, reactivating innate anti-tumor immunity. PP1 inhibition represents a promising therapeutic strategy to enhance anti-myeloma immunity and overcome immune evasion.

Akynzeo 235 mg/0.25 mg concentrate for solution for infusion contains a fixed-dose combination of fosnetupitant (FNET) and palonosetron (PAL). Prior to administration, the Akynzeo concentrate (20 mL vial) is diluted with 30 mL 0.9% sodium chloride infusion solution (NS). According to the Summary of Product Characteristics, ready-to-administer (RTA) infusion solutions are physicochemically stable for 24 hours stored at room temperature. The aim of the study was to investigate the extended stability of FNET/PAL infusion solutions in polyolefin (PO) infusion bags as well as admixtures with 12 mg dexamethasone (DEX) injection solution, diluted with NS and stored at 25°C. FNET/PAL (Akynzeo) and FNET/PAL/DEX test solutions were prepared in triplicate in PO bags prefilled with 30 mL and 100 mL NS and stored protected from light at 25°C in a climate chamber for 28 days. Directly after preparation, on day 1, 2, 3, 5, 14 and 28, test solutions were inspected visually and samples were withdrawn. FNET, PAL and DEX concentrations were determined simultaneously by a newly developed and validated stability-indicating high-performance liquid chromatography assay. In parallel, pH values were measured. Subvisible particles were counted on day 5. Over the 28-day period, FNET and PAL concentrations remained above 99% and above 98% of the initially measured concentrations, respectively. Admixed with DEX, the concentrations of FNET, PAL and DEX remained above 99% of the initially measured concentrations. Results of pH measurement and visual inspection substantiated stability of the test solutions. Subvisible particle counts measured on day 5 of storage fulfilled the specifications of European Pharmacopoeia (Ph. Eur.) 2.9.19. Reconstituted FNET/PAL (Akynzeo) infusion solutions and FNET/PAL/DEX admixtures diluted with 30 mL and 100 mL NS in prefilled PO bags are physicochemically stable for at least 5 days (subvisible particle count specification fulfilled) and 28 days (subvisible particle count not tested) when stored light-protected at 25°C. Results allow pharmacy-based preparation of RTA FNET/PAL and RTA FNET/PAL/DEX infusion solutions in advance.

Long-term glucocorticoid therapy, exemplified by dexamethasone (DEX), frequently induces hepatic steatosis, posing a significant clinical challenge. Yellow tea (YT), a lightly fermented tea, is rich in polyphenols and polysaccharides, yet its protective effects against DEX-induced liver injury remain underexplored. This study investigated the hepatoprotective mechanisms of a yellow tea water extract (YT) using a DEX-induced mouse model, integrated with transcriptomic, metagenomic, and metabolomic analyses. YT intervention (500 mg-1 kg-1 day-1 for 6 weeks) significantly attenuated DEX-induced hepatocellular injury, as evidenced by reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, decreased hepatic triglyceride (TG) and total cholesterol (TC) accumulation, and suppressed systemic inflammation (lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF-α)). Hepatic transcriptomics and subsequent reverse transcription quantitative PCR (RT-qPCR) validation revealed that YT upregulated the antioxidant genes nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) while downregulating the lipogenic gene sterol regulatory element-binding protein 1c (SREBP-1c) and upregulating the fatty acid oxidation gene peroxisome proliferator-activated receptor alpha (PPAR-α). Gut microbiota analysis showed that YT reshaped the microbial community, notably enriching beneficial taxa such as Bifidobacterium pseudolongum and members of the Muribaculaceae family. Serum metabolomics indicated that this microbiota remodeling was associated with the restoration of perturbed metabolic pathways, notably tryptophan metabolism. Correlation analysis further linked specific microbial shifts with improved metabolic and inflammatory markers. Collectively, these integrated transcriptomic, metagenomic, and metabolomic findings demonstrate that YT alleviates DEX-induced hepatic steatosis through dual mechanisms involving direct hepatic antioxidant and lipid metabolic regulation and systemic modulation via the gut-liver axis, positioning it as a promising dietary strategy against glucocorticoid-associated metabolic complications.

Dexamethasone (DEX) is widely used in equine practice for its potent anti-inflammatory effects and diverse studies have examined its pharmacology in horses. We integrated all available pharmacokinetic (PK) and pharmacodynamic (PD) data from 12 studies to quantify DEX disposition and endocrine effects in horses. DEX concentrations in blood, urine and synovial fluid, plus cortisol (CTS) and glucose (GLU) in plasma, following various administration routes (intravenous(IV), intramuscular (IM), intra-articular, oral) were available from original studies or digitized from literature. A minimal physiologically-based PK model and linked indirect response PD models were applied. The mean clearance of DEX was 344mL/h/kg via hepatic metabolism (98%) and renal excretion (2%). Due to nonlinear tissue binding, DEX generally exhibited a prolonged terminal phase in plasma, maintaining concentrations above a designated plasma threshold of 5pg/mL for 67h following 0.05mg/kg IV dose. Dosing input parameters of DEX varied markedly across dosing routes and prodrug formulations (alcohol, isonicotinate, phosphate), with bioavailability ranging 37 ~ 100%. Oral and pro-drug doses produced rapid absorption, except for IM DEX-isonicotinate that exhibited slow (flip-flop) availability. Adrenal suppression with an IC50 of 0.038ng/mL and plasma GLU increases with an EC50 of 0.79ng/mL were observed that commonly persisted for 2 ~ 4days after single dose. This meta-analysis utilized a mechanistic and physiologically-based modeling framework to provide global perspectives that may promote the rational use of DEX in equine medicine and support evidence-based regulatory decisions.

Purpose Glucocorticoid-induced glaucoma (GIG) involves trabecular meshwork (TM) fibrosis, including excess extracellular matrix (ECM) deposition and myofibroblast transdifferentiation, which impairs aqueous humor outflow. Selective laser trabeculoplasty (SLT) is an established and effective treatment for lowering intraocular pressure, yet its underlying cellular and molecular mechanisms remain incompletely understood. We investigated whether SLT can normalize the fibrotic phenotype and restore TM cell function in a steroid-treated primary human cell model. Methods Primary human TM cells were exposed to 100 nM dexamethasone (DEX) for 3 or 7 days, then treated with or without SLT (1.0 mJ). ECM proteins (fibronectin, collagen IV) and myofibroblast markers (α-SMA, vimentin, FSP-1) were analyzed by Western blot and immunofluorescence. Migration (scratch, transwell), phagocytosis (fluorescent beads), and proliferation (EdU) were assessed. Results DEX induced a flattened, myofibroblast-like morphology, ECM accumulation, and elevated myofibroblast marker expression. SLT markedly reduced these changes, approaching control levels in some cases. DEX-enhanced migration was abolished by SLT in scratch (−110% at 3 d, −95% at 7 d; p < 0.001) and transwell assays (−117% at 3 d, −73% at 7 d; p < 0.0001). SLT partially rescued DEX-impaired phagocytosis (+68% at 3 d; p < 0.01) and proliferation (+37% at 3 d; p < 0.001), with reduced efficacy after prolonged exposure. Conclusions SLT mitigates early glucocorticoid-induced TM fibrosis and restores key cellular functions, supporting its potential as a disease-modifying approach for GIG.

The combination of hydrogels and polymeric nanoparticles (NPs) offers a versatile strategy to engineer multifunctional nanocomposite systems for advanced drug delivery applications. In this work, three amphiphilic block copolymers were synthesized through controlled/living polymerizations, affording macromolecules with distinct end-chain functionalities. These copolymers self-assembled into core-shell NPs, which were subsequently embedded within a cross-linked agarose-carbomer-hyaluronic acid hydrogel via physical, chemical, or ionic interactions. The incorporation of NPs within the hydrogel matrix enabled the co-delivery of both hydrophobic and hydrophilic therapeutic cargos, confining dexamethasone (DEX) in the hydrophobic NP core and a model protein within the water-rich hydrogel network. The resulting hybrid systems exhibited tunable rheological and NP release properties, depending on the NP surface moieties and the encapsulation method. Sustained DEX release was displayed over several days, and controllable protein release was achieved according to the NP surface properties. The nanocomposite showed excellent cytocompatibility, demonstrating a relevant reduction of pro-inflammatory cytokines expression in vitro. Overall, the proposed strategy highlights the potential of polymer chemistry-driven design to tailor hydrogel-NP interactions, providing a promising platform for targeted, sustained co-delivery of therapeutics suitable for several applications.

Background: Acute respiratory distress syndrome (ARDS) is a severe lung disorder characterized by intense pulmonary inflammation. Although corticosteroids are the primary anti-inflammatory therapeutic option, increased susceptibility to infection remains a significant clinical concern. Aged garlic extract (AGE) is a natural agent demonstrating anti-inflammatory and antioxidant qualities, and a high safety profile. We investigated the combined effect of AGE and low-dose steroids as a therapeutic approach through AGE-induced anti-inflammatory effects. Methods: Differentiated M1 macrophages were established by stimulating THP-1 cells with lipopolysaccharide (LPS) and interferon-gamma. We assessed inflammatory cytokine release and related signaling to investigate the effects of AGE and/or low-dose dexamethasone (DEX). We also assessed nuclear factor-kappa B (NF-κB) pathway activation using immunoblotting. We evaluated the therapeutic efficacy of AGE by monitoring body weight, quantifying inflammatory cells in the bronchoalveolar lavage fluid (BALF), and histological scoring of lung injury in an ARDS mouse model by intratracheal LPS instillation. Results: AGE significantly inhibited cytokines like Interleukin (IL)-6 and Monocyte chemoattractant protein-1 and suppressed NF-κB phosphorylation. Combining AGE with DEX broadened and enhanced inhibition of inflammatory mediators compared to monotherapy, while further suppressing NF-κB expression. In an ARDS model, the combination of AGE and DEX significantly suppressed LPS-induced body weight loss, inflammatory cell infiltration in BALF, and lung injury. Conclusions: Co-administration of AGE and low-dose DEX effectively suppressed excessive pulmonary inflammation in ARDS. This suggests a novel therapeutic approach that could enhance anti-inflammatory function, simultaneously reducing the adverse outcomes associated with high-dose steroid monotherapy.

The 1 mg overnight dexamethasone suppression test (ONDST) is recommended for the investigation of hypercortisolism and adrenal incidentalomas. Measurement of cortisol and dexamethasone (DXM) has been shown to improve diagnostic sensitivity of the ONDST. Recent work has shown that salivary cortisone collection can be undertaken at home replacing serum sampling, but previous studies have found poor performance of salivary DXM after the ONSDT. Herein we introduce the concept of measuring 11-dehydrodexamethasone (11-DHD): a DXM metabolite produced in the salivary duct by metabolism of 11β-hydroxysteroid dehydrogenase type 2, as a surrogate marker for DXM absorption. Paired 0900h serum and saliva samples (n=90) were collected post-ONDST. Independent liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays were used to measure serum cortisol and DXM. A novel LC-MS/MS assay was developed to measure salivary cortisol, cortisone, DXM and 11-DHD. Results were compared and correlations were assessed using Pearson's correlation coefficient. Serum and salivary DXM results exhibited a poor correlation (R-squared = 0.135). Salivary DXM and 11-DHD also correlated poorly (R-squared = 0.163). Serum DXM and salivary 11-DHD yielded a positive correlation with an R-squared of 0.75. The positive relationship between serum DXM and salivary 11-DHD is novel. At higher concentrations of DXM, the correlation becomes somewhat curvilinear and more variable. A similar relationship is seen between salivary cortisol and cortisone. The development of a salivary 11-DHD LC-MS/MS assay has the potential to improve the current patient pathway. Patients could administer the drug and collect a 0900h-saliva sample at their convenience, prior to posting for analysis.

3,3'-Diindolylmethane ameliorates muscle atrophy by modulating mitochondrial function and calcium homeostasis.

Post-embolization syndrome (PES) is a frequent complication after hepatocellular carcinoma (HCC) treatment. This study compared dexamethasone (DEX) versus N-acetylcysteine (NAC) for efficacy and safety in preventing PES at 48 h after transcatheter arterial chemoembolization (TACE). This Phase 3, randomized (1:1), double-blind, double-dummy, parallel-group, non-inferiority study, included patients with early- to intermediate-stage HCC (BCLC Stages A-B) without macrovascular invasion who were candidates for TACE. Participants were randomly assigned to receive either an intravenous single dose of 8 mg DEX or NAC as part of the periprocedural TACE protocol. A total of 85 patients were included in the outcome analysis. PES incidence was non-inferior between groups (difference proportion DEX-NAC 0.02, [95% CI: -0.13 to 0.17]). However, subgroup symptoms' analysis showed significantly greater reduction in abdominal pain (87.5% vs. 55.3%, p = 0.002) and fever (52.5% vs. 28.9%, p = 0.035) in DEX group compared to NAC group. Liver decompensation was significantly greater reduction in the DEX group than the NAC group (90% vs. 52.6%, p < 0.001). Anaphylactoid reactions (18.4%) were observed exclusively in the NAC group. Multivariate analysis showed preexisting high serum ALT was associated with an increased risk of developing PES (OR: 1.05; 95% CI: 1.01-1.08), and a higher chemotherapy dosage emerged as an independent risk factor for post-TACE liver decompensation (OR: 1.00; 95% CI: 0.84-0.99). PES incidence was non-inferior between groups. However, at 48 h post-TACE, the DEX regimen was associated with a significant reduction in fever, pain, and liver decompensation.