Mannose-decorated N-succinyl chitosan nanoparticle film: A novel approach for enhanced wound healing.

Citrus peels have traditionally been used for their anti-inflammatory properties. Their bioactive compounds can modulate neutrophil activation and reduce ROS production, both of which play key roles in the development of many chronic inflammatory diseases. The present study aimed to investigate the anti-inflammatory potential of an orange peel aqueous extract (OPE) and its major flavonoid, hesperidin (HSP), using integrated in vitro, in vivo, and in silico approaches. The anti-inflammatory activities of OPE and HSP were first assessed in isolated human neutrophils through degranulation and total ROS production assays. In vivo effects were evaluated in male Wistar rats using xylene-induced ear edema and λ-carrageenan-induced peritonitis models. In silico molecular docking analyses were performed to predict the interactions of hesperidin with key inflammatory targets. In vitro, OPE and HSP significantly inhibited ROS production in neutrophils stimulated with PMA and fMLF and markedly reduced neutrophil degranulation. In vivo, pretreatment with OPE or HSP resulted in a substantial decrease in ear edema and neutrophil infiltration in peritoneal exudates, with comparable effects to those of aspirin. Docking results showed strong predicted binding affinities of hesperidin for NADPH oxidase subunits, cyclooxygenases-1 and -2, p38 MAPK, and NF-κB. Collectively, these findings demonstrate that OPE and HSP exhibit potent anti-inflammatory effects via multiple complementary mechanisms, supporting the valorization of citrus by-products as nutritionally relevant functional ingredients with potential applications in the dietary management of inflammation-related disorders.

The consensus molecular subtype 4 (CMS4) of colorectal cancer (CRC) represents an aggressive, mesenchymal phenotype associated with the poorest clinical prognosis. Although angiogenesis is fundamental to CRC progression, current anti-VEGF therapies are frequently compromised by primary or acquired resistance, creating an urgent need to identify alternative vascular drivers. NOTCH3 is significantly enriched in CMS4 CRC, yet its direct role in modulating the tumor vasculature remains elusive. Here, integrating multi-center transcriptomic datasets with clinical validation, we identified NOTCH3 as a critical engine of CRC angiogenesis. In Stage IV clinical samples, NOTCH3 expression correlated significantly with microvessel density (MVD). Functionally, overexpression of the NOTCH3 intracellular domain (NICD3) dramatically enhanced endothelial tube formation and migration in vitro, while driving robust tumor vascularization in xenograft models. Through transcriptomic profiling, we identified the secreted factor transforming growth factor-beta-induced protein (TGFBI) as the essential downstream effector. Mechanistically, we demonstrate that NICD3 physically interacts with and upregulates SMAD3, thereby facilitating the direct transcriptional activation of TGFBI. Crucially, to translate these mechanistic insights, we utilized molecular docking and drug screening to identify the flavonoid Hesperidin (HES) as a potent binder of TGFBI. HES treatment effectively abolished NICD3-driven angiogenesis and suppressed tumor progression in vivo. Collectively, our findings characterize a novel NICD3/SMAD3/TGFBI signaling axis as a key vulnerability in CRC and propose HES as a promising precision therapeutic strategy for CRC patients with features of CMS4.

Hesperidin-loaded Eudragit S100 nanoparticles alleviate ulcerative colitis by repairing intestinal barrier and modulating gut microbiota.

Cisplatin (CDDP) is a widely deployed chemotherapeutic medication used to treat various solid tumors, but its clinical utility is limited by dose-dependent ovarian toxicity. Naringin (NG) and hesperidin (HD) are two naturally occurring flavonoids found in citrus fruits and have protective effects on mitochondrial function. The current study examined the protective effects of NG and HD on CDDP-induced mitochondrial dysfunction and cytotoxicity in granulosa cells. The cells are treated with CDDP alone or with NG or HD. CDDP reduced cell viability, ATP synthesis, oxygen consumption rate (OCR), mitochondrial membrane potential (MMP), and mitochondrial complex functions in a dose-dependent pattern. It also altered mitochondrial dynamics and enhanced glycolytic activity, as exhibited by lactate levels. MMF increased, and fatty acid composition changed, resulting in a higher unsaturated/saturated ratio. PINK1 and PARKIN levels were reduced upon CDDP treatment, suggesting mitophagy disruption. Co-treatment of NG and HD enhanced complex activity, MMP, OCR, ATP generation, and cell viability. MMF was protected by NG and HD, which also stabilized fatty acids and enhanced ion permeability and mitochondrial swelling. Compared to NG, HD preserved numerous attributes more effectively and restored them almost completely. NG and HD effectively preserve mitochondrial bioenergetics, structure, and dynamics in granulosa cells, mitigating CDDP-induced dysfunction. These findings highlight their potential as natural adjuvants to reduce ovarian toxicity and support fertility preservation in female cancer patients.

Introduction/Objective Diabetic cataract is driven by hyperglycemia-associated oxidative/nitrosative stress, inflammation, apoptosis, activation of the polyol pathway, and lens protein glycation. Hesperidin (HSN) and Naringenin (NGN) are citrus flavonoids with antioxidant, anti-inflammatory, anti-apoptotic, and antidiabetic activities. This study evaluated their lens-protective effects in streptozotocin (STZ)-induced diabetic rats. Methods Male Sprague-Dawley rats with STZ-induced diabetes received hesperidin (100 mg/kg/day, orally) or naringenin (50 mg/kg/day, orally) for 10 weeks. Fasting blood sugar, serum insulin, lenticular malondialdehyde, nitric oxide, total antioxidant capacity, TNF-alpha, IL-6, NF-kB p65, Bax/Bcl-2 ratio, cleaved caspase-3, aldose reductase activity, sorbitol concentration, glycated proteins, and total/soluble proteins were assessed. Results STZ significantly increased fasting blood sugar and reduced serum insulin. Diabetic lenses also showed increased levels of malondialdehyde, nitric oxide, TNF-alpha, IL-6, NF-kB p65, Bax/Bcl-2 ratio, cleaved caspase-3, aldose reductase activity, sorbitol, and glycated proteins, with reduced total antioxidant capacity and total/soluble protein levels. HSN and NGN significantly ameliorated these changes versus untreated diabetic rats ( p < 0.05). Discussion The findings indicate that HSN and NGN mitigate biochemical pathways implicated in diabetic lens injury, including oxidative/nitrosative stress, inflammation, apoptosis, polyol-pathway activation, and protein glycation. Conclusion In this STZ-induced rat model, hesperidin and naringenin preserved lens biochemical homeostasis and attenuated diabetes-associated lens injury, supporting their potential as adjunctive candidates for preventing or delaying diabetic lens damage.

Deltamethrin (DLM), a widely used pyrethroid insecticide, has been linked to cardiotoxic effects in non-target organisms. Hesperidin (HSP), a dietary bioflavonoid with antioxidant and cardioprotective properties, may counteract these effects. This study investigated the protective role of HSP against DLM-induced cardiotoxicity in male Wistar Albino rats. Thirty-two rats were divided into four groups: Control, DLM, DLM + HSP 100, and DLM + HSP 300. At the end of the experiment, serum ischemia-modified albumin (IMA), glucose, cholesterol, triglyceride, and HDL levels were analyzed. Cardiac and aortic tissues were assessed histopathologically. Masson's trichrome staining evaluated cardiac fibrosis, Verhoeff-Van Gieson staining examined elastin and tunica media thickness, and caspase-3 expression in the aorta was determined immunohistochemically. DLM administration caused cardiac and aortic damage by increasing IMA, glucose, caspase 3 activities, and tunica media thickness. HSP treatment, particularly at 300 mg/kg, reduced IMA (0.28 ± 0.02 vs. 0.60 ± 0.03 AU), glucose (141.12 ± 11.70 vs. 207.06 ± 9.85 mg/dL), cardiac histopathological damage score (2.17 ± 0.41 vs. 9.02 ± 1.35), tunica media thickness (95.29 ± 4.29 vs. 114.95 ± 17.20 µm), and caspase-3 expression score (0.62 ± 0.74 vs. 2.87 ± 0.35). All results showed significance at the p < 0.05 level. HSP exhibited dose-dependent protective effects against DLM-induced oxidative stress, apoptosis, and cardiovascular injury, suggesting its potential as a therapeutic candidate against pesticide-related cardiotoxicity.

The present study investigated the hepatoprotective effects of hesperidin (HES) encapsulated in chitosan nanoparticles (HES-CNPs) against Malathion (MAL)-induced liver toxicity in rats. Ninety male Wistar rats were randomly divided into six groups: a control group, groups treated with HES (100 mg/kg BW) or HES-CNPs (100 mg/kg BW), a MAL-exposed group (27 mg/kg BW), and two combination groups receiving MAL (27 mg/kg BW) together with either HES or HES-CNPs (100 mg/kg BW) for four consecutive weeks. MAL administration induced profound biochemical and molecular alterations in rats. It significantly reduced serum total protein and its fractions, while elevating hepatic enzyme activities, bilirubin, cholesterol, and triglycerides (TGs). Oxidative stress was evident by decreased activities of antioxidant enzymes (CAT, SOD, GPx), reduced glutathione levels, and increased malondialdehyde and reactive oxygen species (ROS). At the molecular level, MAL exposure upregulated proapoptotic genes (p53, Bax, caspase-3, caspase-9) and inflammatory markers (TNF-α, NF-κB), while down-regulating the antiapoptotic gene Bcl-2 and the cytoprotective gene Nrf2. Exposure to MAL significantly increased hepatic DNA oxidative damage, as indicated by elevated 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels and DNA fragmentation. Treatment with HES-CNPs provided significantly greater protection than crude HES (p < 0.05). These hepatoprotective effects were evidenced by normalization of liver function biomarkers and lipid profile, restoration of antioxidant enzyme activities and glutathione levels, reduction of lipid peroxidation, suppression of proinflammatory and proapoptotic markers, upregulation of Nrf2 and Bcl-2, attenuation of DNA oxidative damage (8-OHdG) and fragmentation, and marked improvement of hepatic histoarchitectural and ultrastructural integrity. HES demonstrated strong binding affinity toward key proteins involved in oxidative stress, apoptosis, and inflammatory pathways, as revealed by in silico studies. In conclusion, HES-CNPs demonstrated improved hepatoprotection against MAL toxicity through the activation of the Nrf2/HO-1 antioxidant pathway and the inhibition of NF-κB/p53-mediated inflammation and apoptosis.

Hesperidin (HSP) is a bioactive flavonoid, and its activity is limited due to poor water solubility. We designed this research to develop and evaluate hesperidin nanoparticles (HSPNPs) to enhance drug release and therapeutic efficacy. HSPNPs were prepared by the magnetic stirring and probe sonication techniques using the glyceryl monostearate, chitosan, poloxamer 188 and D- α-tocopheryl polyethylene glycol succinate. The developed HSPNPs were characterized for the particle size (PS), surface charge (ZP), encapsulation efficiency (EE), drug load (DL), and other physicochemical assessments. Finally, the optimized HSPNPs2 was further evaluated for in-vitro dissolution, antioxidant, anti-inflammatory activities, as well as an ex-vivo permeation study. The results were supported by the findings of a molecular docking study on the anti-inflammatory (iNOS oxygenase) and antioxidant receptors (glutathione transferase and superoxide dismutase). HSPNPs displayed the PS between 175 and 275 nm, PDI values ˂0.05, ZP (˃ 20 mV), EE (69.9 ± 3.8 to 90.3 ± 5.3%), DL (7.2 ± 0.8 to 9.5 ± 1.1%) and a prolonged drug release (71.1 ± 4.6% in 24 h) with Higuchi release order kinetics. DSC and XRD studies reveal the conversion of crystalline HSP into an amorphous form. The in vitro antioxidant and anti-inflammatory results showed concentration-dependent activity. An excellent molecular docking score was observed for antioxidant (-5.41 kcal/mole for GSH and − 5.15 kcal/mole for SOD) and anti-inflammatory (-5.85 kcal/mole for iNOS) receptors. Based on the results, we can say that the GMS- and CHT-based nanoparticles could be a beneficial way to deliver HSP by oral route so that its solubility can be enhanced and it exhibits better biological effects.

Integrating spectroscopic techniques and molecular dynamics simulations to probe the interaction between hesperidin and soy protein isolate and the consequent functional improvements.

To analyze Hesperidin (HES) in its pure form and in supplement formulations, a new spectrophotometric method was developed using a flow injection system (FI) as an integrated, semi-automated technique for quantitative analysis. An orange-colored product was produced during the reaction of HES with diazotized Procaine penicillin (PRP), and was spectrophotometrically detectable at 434nm wavelength (HES–N=N–PRP). The optimum conditions for the Flow injection method were established after evaluating all relevant chemical and physical parameters. The linearity range (LR), the correlation coefficient(r), limit of detection (LOD), and limit of quantification (LOQ) were obtained at 5 -100 μg mL-1, 0.9936, 0.679 μg mL-1, and 1.86 μg mL-1, respectively, for 79 samples per hour. The Azo bond (R-N=N-R) was obtained between the HES ring (nucleophilic) and diazotized PRP (electrophile). So, the reaction creates a highly conjugated chromophore that forms an intensely colored azo compound dye. The procedure demonstrated successful applicability for HES quantification in pharmaceutical formulations. Finally, the environmental sustainability of the developed method was assessed using complex MoGAPI and AGREE Preparation techniques. The evaluation confirmed that the approach is both environmentally friendly and aligned with green analytical principles.

Bone defects remain a major clinical challenge because of their limited self-healing capacity. This study aimed primarily to evaluate whether nanoscale modified borate bioglass scaffolds (MBBGS) could enhance the delivery of hesperidin (HPN), an antioxidant flavonoid, to bone defects, and secondarily to compare the osteogenic effects of micro- and nano-sized HPN (mHPN and nHPN) on bone regeneration. Scaffolds were fabricated and fully characterized. Fifty-six healthy male albino rats were anesthetized, and bilateral critical-sized calvarial defects were created. The rats were divided into four groups: control (empty defects), MBBGS alone, MBBGS loaded with mHPN, and MBBGS loaded with nHPN. The animals were euthanized at the end of the 2nd and 6th weeks postoperatively. The skulls were harvested and processed for radiological, histological, and immunohistochemical analyses. Radiographic evaluation showed progressive defect closure over time, with the greatest reduction in defect size observed in the MBBGS + nHPN group compared to the other groups. Histologically, the MBBGS + nHPN group revealed the greatest osteogenic impact and significantly increased osteopontin (OPN) immunoreactivity, followed by MBBGS + mHPN and MBBGS groups, while the control group exhibited minimal bone healing and weak OPN reactivity. In conclusion, the newly fabricated MBBGS effectively promoted calvarial bone regeneration, which was further enhanced by loading with nHPN.

Objective Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder for which current therapeutic options are often insufficient. This study aimed to evaluate the therapeutic potential of hesperidin (HSP), in suppressing complete Freund's adjuvant (CFA)-induced RA in Wistar albino rats, through modulation of key pro-inflammatory markers (TNF-α, IL-6, IL-1β, NF-κB, and COX-2), supported by in silico docking and pharmacokinetic profiling. Methods Forty-eight female Wistar albino rats were randomized into six groups (n = 8). Group 1 received normal saline; Group 2 was induced with RA via 0.1 ml CFA and left untreated; Group 3 received CFA + naproxen (8 mg/kg). Groups 4, 5, and 6 received hesperidin at 100, 200, and 400 mg/kg, respectively, following RA induction. Serum pro-inflammatory markers were quantified using standard biochemical assays. Molecular docking was performed to assess HSP binding affinity toward COX-2, TNF-α, IL-1β, and IL-6, while ADMET profiling was carried out to predict pharmacokinetic and toxicity attributes. Results In vivo results revealed that RA induction significantly elevated TNF-α, IL-6, IL-1β, and NF-κB levels ( p &lt; .05) across the treated groups. Whereas, hesperidin treatment produced a dose-dependent and significant ( p &lt; .05 ) reduction in these markers, restoring them to levels comparable to naproxen-treated rats. In silico docking analysis revealed that hesperidin has multi-target binding capability inhibitor to COX-2, TNF-α, IL-1β, and IL-6. Protein-ligand binding was predominantly surface-oriented except for COX-2, which showed interior pocket binding. ADMET predictions indicated that HSP is a P-glycoprotein substrate with low gastrointestinal absorption, does not cross the blood–brain barrier, shows no cytochrome P450 enzyme subunit inhibition, and lacks carcinogenic or hepatotoxic potential. Conclusion Combined in vivo and in silico findings demonstrate that hesperidin exhibits strong anti-inflammatory effects by inhibiting key mediators of RA pathogenesis, alongside a favorable safety pharmacokinetic profile.

Cisplatin (CSP) is a first-line chemotherapeutic for laryngeal squamous cell carcinoma (LSCC), but its clinical effectiveness is limited by resistance and toxicity. Hesperidin (HESP), a citrus flavonoid, may enhance chemotherapeutic efficacy through pro-apoptotic properties. This study investigated the involvement of the transient receptor potential melastatin-2 (TRPM2) channel in the HESP-mediated potentiation of CSP-induced cytotoxicity in human laryngeal carcinoma (Hep-2) cells. Hep-2 cells were treated with CSP (25 µM), HESP (25 µM), or their combination for 24 h. The findings showed that the combined application of HESP and CSP reduced cell viability by approximately 50% (p < 0.001), which was the lowest compared to CSP alone. Western blot analysis revealed that TRPM2 protein expression was higher in the CSP+HESP group compared to the control group (p < 0.001). This synergistic treatment resulted in an increase in ROS production and a decrease in MDA levels, accompanied by a reduction in cellular GSH levels (p < 0.001). Furthermore, the combination therapy increased pro-inflammatory cytokines such as IL-1β and TNF-α (p < 0.001). Functional analyses showed that HESP treatment enhanced CSP-induced Ca2+ influx and altered mitochondrial membrane potential (p < 0.001). The pharmacological inhibition of TRPM2 with ACA and 2-APB reversed these effects, restoring redox balance and reducing cellular damage. In conclusion, HESP amplifies CSP-induced apoptosis in Hep-2 cells through TRPM2-dependent oxidative stress, Ca2+ dysregulation, and mitochondrial dysfunction. These findings identify TRPM2 as a mechanistic mediator of HESP-enhanced chemosensitivity in LSCC.

Liver fibrosis is characterized by an excessive accumulation of extracellular matrix (ECM) proteins as a wound-healing response to chronic liver injury, leading to tissue scarring and organ dysfunction. Natural compounds, including phytonutrients and polyphenols, have been shown to exert protective effects by reducing profibrotic biomarkers in vitro and in vivo models. Here, we provide the first evidence that the polyphenol hesperidin (HE) can counteract the onset of fibrotic responses in an ex vivo mouse liver fibrosis model induced by Transforming Growth Factor-β1 (TGF-β1) (5 ng/mL). Notably, HE drives early ECM remodeling in the fibrotic mouse liver tissue. Fibrosis-related parameters were assessed at both the transcriptional and translational levels after treatment with HE at increasing concentrations of 50, 75, and 100 µg/mL. Interestingly, HE at 75 µg/mL exerted the strongest beneficial effect, significantly decreasing the gene expression of α-SMA, SERPINH-1, FN-1, VIM and COL1A1 and counteracting the TGF-β1-induced upregulation of key fibrotic markers, including α-SMA, COL1A2, and VIM, reflecting its capacity to attenuate myofibroblast activation and ECM production and modulating membrane lipid peroxidation. Furthermore, HE inhibited SMAD2 phosphorylation, suggesting that its antifibrotic activity may involve the modulation of the TGF-β/SMAD signaling pathway. Moreover, it promoted an anti-inflammatory response, due to a decrease in IL-1β and IL-6 expression. Our study highlights the potential of the ex vivo model as a platform for evaluating the antifibrotic efficacy of natural molecules, and it suggests significant translational implications and new opportunities for developing innovative therapeutic strategies.

Pentagamavunon-1 (PGV-1) is a potential anticancer candidate due to its specific targeting of cancer cells with minimal toxicity to normal cells. This study examined the potency of hesperidin (HSD) in improving the anticancer effects of PGV-1 for triple-negative breast cancer (TNBC). The 4T1 and NIH-3T3 cell lines were used as the model of TNBC and normal fibroblast, respectively. The cytotoxicity was quantified using MTT and clonogenic assays, whereas the cell cycle and apoptosis were measured by flow cytometry. Cell migration was assessed by scratch-wound healing assay. Senescence was measured using the SA-β-gal assay, and the secretion of matrix metalloproteinase (MMP)-2 and 9 was examined using gelatin zymography. Protein expression level was analyzed through capillary Western blot. The collected data were quantified using one-way ANOVA. PGV-1 significantly reduced 4T1 cell viability, with IC50 values of 7 and 2 µM at 24 and 48 h, respectively. Its cytotoxic effect persisted up to 7 days after removal. HSD alone showed no cytotoxicity against 4T1 cells, but in combination with 1 µM of PGV-1, it synergistically enhanced cell growth inhibition and apoptosis induction. This synergism is likely due to ERK1/2 phosphorylation inhibition, leading to reduced levels of Bcl-2 and elevated levels of Bax. In NIH-3T3 cells, higher concentration PGV-1 (10 µM) induced early senescence-associated features, but 100 µM HSD prevented this and suppressed MMP-2 and 9 secretion. PGV-1 and HSD combination demonstrates potential as a co-treatment strategy for effective anticancer therapy while preserving normal cell integrity.

Oxidative stress and neuroinflammation are key components in neurodegenerative diseases, where early intervention using natural treatments may offer neuroprotective effects. This study shows that isoliquiritigenin (ISL), hesperidin (HES), and curcumin (CUR) can mitigate lipopolysaccharide (LPS)-induced neuroinflammation and oxidative stress in vitro and in vivo. The compounds were initially tested for cytotoxicity and found to reduce nitric oxide (NO) production, especially CUR and ISL. They were able to restore antioxidant enzyme activities both in vivo and in vitro. All treatments reduced inducible nitric oxide synthase (iNOS) expression compared to the untreated LPS control group. Behavioral assessments indicated that LPS impaired spatial and nonspatial memory, but treatments improved cognitive performance. Biomarker analyses revealed that ISL, HES, and CUR reduced the interleukin (IL)-1β and nuclear factor erythroid 2-related factor 2 (Nrf2) ratio in the hippocampus. Moreover, they decreased the level of caspase-3 demonstrated by western blotting and tumor necrosis factor-α (TNF-α) level. Thereby they inhibited LPS elicited apoptosis. Likewise, their anti-inflammatory effects were illustrated in the histopathological examination. Furthermore, they decreased the expression of amyloid-β. The study reinforces the potential of these natural compounds as protective and therapeutic cost-effective alternatives for managing neuroinflammation and neurodegeneration.

Electrospun poly (vinyl alcohol)/zein-based nanofibrous dressings co-loaded with pramipexole and hesperidin for diabetic wound management: In silico, in vitro, and in vivo assessments.

Nitric oxide (NO) was previously thought to have a beneficial role in hair growth, but it is unclear whether NO donors can encourage hair development. Therefore, this study aims to systematically investigate the physiological mechanisms underlying the therapeutic effects of NO donors in alopecia. We first screened the chemical targets of seven types of NO donors from DrugBank and SwissTargetPrediction, and further identified the differentially expressed genes (DEGs) of three types of alopecia from the GEO database. Integrated bioinformatic analysis was subsequently performed to comprehensively reveal potential pathways. A total of 339 chemical targets of NO donors were collected and 237, 266, and 1158 DEGs of androgenic alopecia (AGA), alopecia areata (AA) and central centrifugal cicatricial alopecia (CCCA) were identified in this study. We further extracted 20 CCCA-related targets from the intersection of 339 targets and 1158 DEGs of CCCA for the following analysis. Through integrative analysis, we found that hesperidin (HP) may exert dual regulatory effects on apoptosis and senescence pathways in hair follicle cells through its specific interactions with BCL2, MAPK8, MMP13 and AURKB, effectively mitigating hair loss. Overall, our work elucidates the molecular mechanisms of NO donors-mediated hair follicle protection, which could pave the way for future investigations into NO-based interventions and their potential clinical applications.

Background & Aim: Preservation ofrenal morphologyand function is essential in rhabdomyolysis (RM)-induced acute kidneyinjury (RIAKI) for which there is no established treatment. Hesperidin(HSP), a natural bioflavonoid with antioxidant and anti-inflammatorypotential, seems promising for RIAKI prevention. Here, we evaluatedthe nephroprotective potential of HSP and compared it with its polylactic-co-glycolic acid (HSP-PLGA) nanoformulation in RM. Methodology: HSP-PLGA was developed by nanoprecipitationand validated by zeta potential, scanning electron microscopy, andFourier-transform infrared analysis. BALB-c mice were pretreated withintraperitoneal HSP and HSP-PLGA. RM was induced using intramuscularglycerol. Serum lactate dehydrogenase (LDH), creatine kinase (CK),creatinine, and urea were estimated. H&E, PAS, and immunohistochemistryfor hemoxygenase-1, tumor necrosis factor (TNF-α), and induciblenitric oxide synthase (iNOS) were done. Tissue levels of lipid peroxidation(LP), superoxide dismutase (SOD), reduced glutathione (GSH), and nitricoxide (NO) were determined. ELISA was used to estimate interleukin-6(IL-6), interleukin-10 (IL-10), and interferon-γ levels. Results: A significant increase in serum CK, LDH, urea,and creatinine validated the RIAKI model. Treatment with HSP and HSP-PLGAsignificantly reduced serum urea and creatinine levels. Interventionalso enhanced antioxidant defense by lowering LP and NO, and increasingSOD and GSH levels. HSP and HSP-PLGA reduced inflammation by suppressingTNF-α, iNOS, IL-6, and interferon-γ, and increasing IL-10.Histologically, this translated into reduced hyaline casts and tubularnecrosis. These promising findings were validated by increased expressionof the protective enzyme hemeoxygenase-1, thus highlighting the compound’spotential in mitigating RIAKI. Moreover, nanoeffect calculation ondifferent parameters exhibited more pronounced effects of HSP-PLGAover HSP. Conclusion: HSP decreases oxidative stressand inflammation, thus preserving renal morphology and function. HSP-PLGAenhances the nephroprotective effects of HSP.