Anti-ulcerogenic potential of lithospermic acid B on NSAID-induced gastric injury in rats

Anti-ulcerogenic potential of lithospermic acid B on NSAID-induced gastric injury in rats Farrah Rasool Jaafar1, Ali Jihad Hemid Al-Athari2, Muayad Sraibet Abbood3, Hayder Ridha-Salman2, Haitham Mahmood Kadhim1,4 1 Department of Pharmacology, College of Medicine, Al-Nahrain University, Baghdad, Iraq 2 College of Pharmacy, Al-Mustaqbal University, Hillah 51001, Babylon, Iraq 3 Department of Applied Embryology, High Institute for Infertility Diagnosis and Assisted Reproductive Technologies, Al-Nahrain University, Baghdad, Iraq 4 Department of Pharmacy, Dijlah University College, Baghdad, Iraq Corresponding author: Hayder Ridha-Salman (h[email protected]m) Received 7 August 2025♦ Accepted 8 November 2025♦ Published 5 December 2025 Citation: Jaafar FR, Al-Athari AJH, Abbood MS, Ridha-Salman H, Kadhim HM (2025) Anti-ulcerogenic potential of lithospermic acid B on NSAID-induced gastric injury in rats. Pharmacia 72: 1–11. https://doi.org/10.3897/pharmacia.72.e167996 Abstract Background: Stomach ulceration is a common side effect of long-term NSAID use. Lithospermic acid B (LAB, sometimes identified as salvianolic acid B) is a phytochemical extracted from Salvia species and has been shown to possess strong antioxidative, anti-inflammatory, and tissue-regenerative capacities. Objective: This research intended to assess the therapeutic effect of LAB on diclofenac-driven gastric injury in male rats. Methods: Forty rats (n = 10/group) were arbitrarily assigned to four groups as follows: normal control (DMSO), induction/model (single diclofenac 100 mg per kg + DMSO), LAB (LAB 20 mg per kg daily), and esomeprazole (Eso; 20 mg per kg each day) for 2 weeks. Results: Diclofenac remarkably (p < 0.05) raised MDA and LPO levels 2.6 and 2.3 times, correspondingly (p < 0.05), while decreasing SOD and CAT activity by 48% and 42%, respectively. LAB treatment resulted in a substantial decrement of MDA and LPO production (45% and 39%), while restoring SOD and CAT activities back to the control (p < 0.05). It further reduced IL-6 (−52%) and increased IL-10 (+63%), in addition to the marked increase of VEGF (+57%) and HGF (+49%) versus diclofenac induction. A marked reduction of mucosal sloughing, edema, and vascular congestion was supported by histopathological outcomes. Conclusion: The pro-angiogenic, anti-inflammatory, and antioxidant capacities of LAB suggest that it offers effective defense against gastric damage caused by NSAIDs. These results validate LAB as a potential natural treatment for NSAID-evoked stomach ulcers. Keywords Diclofenac, gastric ulceration, lithospermic acid B, NSAIDs, salvianolic acid B Introduction Peptic ulcer is a prevalent gastrointestinal disease that presents with a breakdown in the mucosa of the stomach or the first part of the small intestine, causing ulcers that may result in pain, bleeding, and perforation. The ulcer pathophysiology is an intricate phenomenon that may be impacted by a disequilibrium between combative forces, notably stomach acid, pepsin, and ROS, and defensive processes, such as mucosal blood flow, mucus secretion, Copyright Jaafar FR et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Pharmacia 72: 1–11 DOI 10.3897/pharmacia.72.e167996 Research Article Jaafar FR et al.: Lithospermic acid B mitigates rat model of NSAIDs-induced gastric injury2 and antioxidant defenses (Al-Razzuqi et al. 2018; Muhaibes et al. 2025). Epidemiologic investigations demonstrate that peptic ulcer is still a worldwide disease entity, and significant morbidity and severe economic costs have been found in populations chronically exposed to substances causing this condition (Al-Zubaidy and Khalil 2022). Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the major etiologies in the pathogenesis of gastric ulcerations. These drugs, widely used in clinical applications, such as diclofenac, have been reported to block the cyclooxygenase (COX) enzymes, thus resulting in a blockade of the synthesis of prostaglandin, which is essential for the mucosal integrity of the stomach (Amanullah et al. 2022). Oxidative stress, inflammation, and breakdown of the mucosal barrier are consequences of such imbalance that eventually cause damage to gastric tissues. Because of widespread use of NSAIDs for pain and inflammatory conditions, there is an imperative requirement to develop effective measures for the prevention and therapy of NSAID-induced gastric ulcers (Essam Hameed et al. 2022; Abdul-Majeed and Al-Atrakji 2025). Traditional treatments, such as proton pump inhibitors and H2-receptor antagonists, act mainly through gastric acid suppression. Although these agents decrease ulcer generation, they have no direct effect on oxidative stress or inflammatory pathways and also do not induce tissue repair or angiogenesis – decreasing the range of protection (Mo et al. 2015). Natural polyphenolic compounds have received much attention as possible protective agents in various conditions due to their role in modulating several pathogenic pathways (Abdul-Majeed et al. 2025; Hassan et al. 2025). Lithospermic acid B (LAB), one of the most important bioactive compounds isolated from Salvia miltiorrhiza, shows a powerful antioxidant effect and down-regulation of chemotactic cytokines, comprising tumor necrosis factor (TNF)-α and interleukin (IL)-1β, while facilitating vascular endothelial growth factor (VEGF)-mediated angiogenesis (Wang and Hu 2018; Zhao et al. 2023). LAB modulates key pathways, including MAPK, JNK, and p38, to inhibit inflammation and apoptosis. It also regulates the transcription of apoptosis indicators such as Bax, Bcl-2, and caspase-3 (Wang et al. 2019; Mao et al. 2024). Its low acidity and ability to dissolve in water have made it useful in various pharmaceutical preparations, comprising injectable formulations (Cheng et al. 2023). These characteristics indicate that LAB may provide a multi-targeted protective role in gastric injury, beyond the protective mechanisms of acid-neutralizing therapies. Even though accumulated evidence has demonstrated that LAB exerts pharmacological effects on cardiovascular, hepatic, lung, and renal models (Kadhim and Al-Mosawi 2021; He et al. 2023), its utilization in the prevention or remedy of NSAID-provoked gastric injury has barely been investigated. Hence, the purpose of the current observation is to figure out the gastrotherapeutic impact of LAB on NSAIDevoked gastric injury in rats and to provide new insights into the multi-target mechanisms of LAB as a natural antiulcerogenic medication in comparison with the standard therapy esomeprazole. The structural formula of LAB is depicted in Fig. 1. Materials and methods Animal preparation Forty male Wister-albino rats (180–250 g) were utilized in the investigation, acquired from Al-Nahrain University, College of Medicine. Rats were preserved in acrylic enclosures of 21 × 24 × 36 cm, each housing 3 animals. Animals were fed conventional pelleted foods and had full utilization of water. Preceding the trial, the rats had been acclimatized for 7 days pursuant to regulated circumstances involving temperature (22 ± 4 °C) and a 12-hour light/12-hour darkness rhythm. The laboratory house was equipped with an airborne vacuuming device to sustain setting parameters. Experimental protocol Forty rats were haphazardly distributed by a computer-generated sequence to the 4 experimental groups (n = 10 per group) according to the power calculation of previous studies. Groups were separated as follows: Group 1 (healthy control): Apparently healthy rats had to get solely dimethyl sulfoxide (DMSO) orally for 2 weeks. Group 2 (induction group): Gastric ulcerations were generated by starving the rats for 24 hours and then giving them a single oral dosage of diclofenac sodium (100 mg per kg) (Berenguer et al. 2006). Subsequently, DMSO had been applied via the oral route for 2 weeks. Figure 1. Lithospermic acid’s structural formula. Pharmacia 72: 1–11 3 Group 3 (LAB group): Ulcers were induced as in Group 2. Afterward, rats received LAB orally at 20 mg per kg daily for 2 weeks (Qiao and Xu 2016). Group 4 (Eso group): Served as a positive control. Ulcers were induced as in Group 2, followed by oral administration of esomeprazole at 20 mg per kg daily for 2 weeks (Boushra et al. 2019). Rats were euthanized on day 15 of the trial, applying an intraperitoneal mixture of xylazine (9 mg per kg) and ketamine (90 mg per kg). Diclofenac sodium (50 mg, Lifepharma, UAE) was mixed in 2.5 mL of purified water to make a 20 mg/mL oral suspension. LAB (Royal-China) was modified by dissolving it in DMSO to yield a 50 mg/ mL oral solution. The sample size (n = 8 per group) represented an adequate statistical power (80%, α = 0.05), estimated by other studies (Soylu et al. 2008). Sample collection Gastric tissue homogenates were prepared by utilizing chilled phosphate-containing buffering saline in a ratio of 1:10 (adding 9 mL of phosphate buffer into 1 g of recently collected tissue) via a tissue homogenizer. The tissue homogenate was then centrifuged for 10 min at 4000 rpm (Jaafar et al. 2018; Tofiq and Idan 2024). The supernatant was aliquoted into sterile microtubes and retained at −80 °C to measure oxidative, inflammatory, and angiogenic bio-indicators via the ELISA technique. ELISA technique Enzyme-linked immunosorbent assays (ELISA) include a combination of specific antibodies with a sensitive simple enzyme assay, mostly containing enzyme-labeled antibodies or antigens, and the activity of enzymes measured colorimetrically. The change in light absorption occurring after the addition of substrate is measured and converted to a numeric value (Ali et al. 2025; Luty et al. 2025). In sandwich ELISA, the target antigen is measured by sandwiching it between two specific antibodies, i.e., a capture and a detection antibody. For successful detection, the antigen must be a compound comprising at least two different epitopes by means of which it can be simultaneously bound by the antibodies. Monoclonal or polyclonal antibodies may be used as the capture or detection antibody in this method, depending on how the assay was developed (Dawood and Abu-Raghif 2024; Motib and Idan 2025). Gastric Histopathological Examination Following organ preservation with 10% buffered formalin, stomach tissues were analyzed (Abbod et al. 2014; Jaafar et al. 2019). A Leica semi-automated rotary microtome was utilized for sectioning the tissues and trimming. After that, the thickness of the section was adjusted to 4 μm for each hematoxylin and eosin. A modified lesion severity score for all groups was based on the histopathological grades of Toktay and Selli (2022) as follows: 0 = no ulcer, 1 = slight hyperaemia, 2 = moderate to marked hyperaemia, 3 = desquamation covering roughly one-third of the mucosal surface, 4 = desquamation occupying two-thirds of the mucosal surface, 5 = submucosal swelling, 6 = blood vessel engorgement. A double-blinded histological assessment was done by two experienced pathologists in order to minimize observer bias (Toktay and Selli 2022). Statistical analysis Data were reflected as the mean (M) ± standard error of the mean (SEM). Data were statistically analyzed using SPSS software (26). The comparisons among 3 or more categories were evaluated by one-way analysis of variance (ANOVA), followed by performing the least significant difference (LSD) post hoc test. If the difference between groups was smaller than 0.05, it had been deemed of statistical significance. Results Effect of LAB on oxidative stress markers The induction group showed a noteworthy elevation in lipid peroxide (LPO) level versus the untreated controls (p < 0.05). LPO amount decreased substantially in the LAB group versus the induction group (p < 0.05) and non-significantly versus the Eso group (p = 0.793 and 0.915, respectively), as shown in Fig. 2. The induction group elevated the malondialdehyde (MDA) level markedly relative to controls (p < 0.05). The LAB group revealed a considerably decreased MDA level compared with the induction group (p < 0.05), but still significantly higher than the Eso group (p < 0.05), as shown in Fig. 2. The induction group displayed a marked decrement in superoxide dismutase (SOD) activity compared to the controls (p < 0.05). The LAB group revealed a marked elevation in SOD level as opposed to the induction/model group and non-markedly to the Eso group (p = 0.763 and 0.617, respectively), as shown in Fig. 2. Concerning catalase (CAT) level, the induction group exhibited a substantial decline in CAT activity compared to controls (p < 0.05), and the LAB group showed remarkable augmentation in CAT level in relation to the induction group and non-substantially to the Eso group and controls (p = 0.659 and 0.730, respectively), as depicted in Fig. 2. Effect of LAB on inflammation-associated parameters IL-6 levels were upregulated markedly in the induction group juxtaposed with controls (p < 0.05). The LAB group decreased the IL-6 level significantly when juxtaposed to the induction group (p < 0.05) and non-substantially to the Eso group (p = 0.564), as seen in Fig. 3. Jaafar FR et al.: Lithospermic acid B mitigates rat model of NSAIDs-induced gastric injury4 Considering the IL-10 level, the induction group showed a substantial diminution contrasted to controls (p < 0.05). The LAB group raised the IL-10 level substantially compared to the induction group (p < 0.05) and non-significantly to the Eso group (p = 0.291), as presented in Fig. 3. Effect of LAB on pro-angiogenic markers Vascular endothelial growth factor (VEGF) level was dramatically reduced in the induction group relative to controls (p < 0.05), while the LAB group presented considerable elevation in VEGF level relative to the induction group (p < 0.05) and non-considerably to the Eso group (p = 0.877), as indicated in Fig. 4. Hepatocyte growth factor (HGF) level was considerably reduced in the induction group when matched to controls (p < 0.05), while the LAB group showed a substantial increment in HGF level when matched to the induction group (p < 0.05) and was non-significant to the Eso group (p = 0.858), as revealed in Fig. 4. However, a summary table of key biomarkers is presented in Table 1. Effect of LAB on NSAID-evoked stomach histological abnormalities On microscopic examination of the control group, the ulcer score was 0, and a normal architecture of the stomach tissue was identified, as described in Figs 5, 6A. The model/induction group had a considerably greater ulcer score than the controls (p < 0.05), indicating a substantial disruption of two-thirds of the gastric epithelium, as well as submucosal edema and vascular congestion, as viewed in Figs 5, 6B. LAB reported an important reduction in ulcer index, as well as a strengthened stomach healing effect, as seen by mitigated mucosal desquamation (shedding) and the presence of mild submucosal edema, reflected in Figs 5, 6C. The esomeprazole-treated group demonstrated a dramatically lowered ulcer index relative to the model/induction group (p < 0.05), showing extensive recovery of gastric tissue, clearly reflected by the absence of desquamation, an attenuated shedding pattern, and no signs of infiltration of inflammatory cells, as revealed in Figs 5, 6D. Figure 2. Impact of LAB on oxidative markers in NSAID-induced gastric injury. Results were displayed as mean ± SEM. Different lowercase letters represent significant variations across groups. A p-value < 0.05 denotes a substantial variation. The symbols “Eso” signify the esomeprazole group, “ind” the induction group, and “LAB” the lithospermic acid B group. - 0 200 400 600 800 1000 1200 control ind. LAB Eso. LPOnmol/g b 0 5 10 15 20 25 30 35 40 control ind. LABEso. MDAnmol/g b a c d 0 2 4 6 8 10 12 14 16 control ind. LAB Eso. SOD unit/mg b a 0 1 2 3 4 5 6 7 8 9 control ind. LABEso. CAT unit/mg b a a a a a a aa Pharmacia 72: 1–11 5 Figure 3. Impact of LAB on inflammation-related markers in NSAID-induced gastric injury. Results were displayed as mean ± SEM. Different lowercase letters represent significant variations across groups. A p-value < 0.05 denotes a substantial variation. The symbols “Eso” signify the esomeprazole group, “ind” the induction group, and “LAB” the lithospermic acid B group. 0 50 100 150 200 controlind. LABEso. IL-6 pg/mg a b 0 50 100 150 200 250 controlind.LAB Eso. IL-10pg/mg b a c ca a Figure 4. Impact of LAB on pro-angiogenic markers in NSAID-induced gastric injury. Results were displayed as mean ± SEM. Different lowercase letters represent significant variations across groups. A p-value < 0.05 denotes a substantial variation. The symbols “Eso” signify the esomeprazole group, “ind” the induction group, and “LAB” the lithospermic acid B group. 0 50 100 150 200 250 controlind. LABEso. VAGF pg/mg b a 0 1000 2000 3000 4000 controlind.LAB Eso. HGFpg/mg b a aa a a Table 1. A summary table describing the key biomarkers and ulcer score. Results were displayed as mean ± SEM. Different lowercase letters convey group differences. A substantial difference is determined by a p-value < 0.05. Parameter Control induction LAB Esomeprazole LPO nmol/g 426.125 ± 37.19a945.75 ± 36.57b439.75 ± 35.96a434.25 ± 33.99a MDA nmol/g 12.375 ± 1.01a36.625 ± 0.88b27 ± 0.65c22 ± 0.53d SOD unit/mg 14 ± 0.59a7.1375 ± 0.58b14.265 ± 0.76a13.825 ± 0.38a CAT unit/mg 7.75 ± 0.38a4.6875 ± 0.43b7.4625 ± 0.63a7.6875 ± 0.39a IL-6 pg/mg 95.5 ± 6.541a168.625 ± 8.093b130.875 ± 5.832c136.25 ± 3.745c IL-10 pg/mg 207.125 ± 7.607a100.625 ± 3.774b191.125 ± 5.269a179.75 ± 6.664a VEGF pg/mg 187.75 ± 6.111a83.5 ± 3.959b182.875 ± 5.187a176.125 ± 6.317a HGF pg/mg 2614 ± 195.987a1511.25 ± 205.994b2931.25 ± 197.298a2801.625 ± 185.788a Ulcer score 0a12.5 ± 0.56b8.25 ± 0.61c7.5 ± 1.45c Discussion NSAIDs are frequently prescribed for pain and inflammation but commonly cause gastrointestinal complications, mainly due to oxidative stress, inflammation, and mucosal ischemia. The present work studies the therapeutic impact of LAB on NSAID-evoked gastric injury in rats. The results demonstrated that LAB notably alleviated the diclofenac-driven oxidative, inflammatory, and histopathological changes, showing profound gastroprotective effects as contrasted with the standard drug esomeprazole. Jaafar FR et al.: Lithospermic acid B mitigates rat model of NSAIDs-induced gastric injury6 Oxidative stress and antioxidative enzyme profiling The existing study’s results suggested that diclofenac treatment led to an enormous rise (p < 0.05) in LPO and MDA productions and a remarkable reduction (p < 0.05) in antioxidative enzymes, involving SOD and CAT. This profile suggests increased oxidative stress and decreased antioxidant capacity, which is considered one of the mechanisms involved in cologastric ulcerative injury (Contreras-Zentella et al. 2017; Jaafar and Abu-Raghif 2023). These findings are in agreement with Saiah et al. (2018) and Abdul-Majeed (2025), who described that NSAIDs induce the overproduction of ROS and increase lipid peroxidation in gastric tissues, resulting in membrane damage and cell necrosis (Saiah et al. 2018; Sharif et al. 2025). The declines in SOD and CAT levels were recorded by earlier reports, suggesting that downregulation of antioxidant molecules by diclofenac could worsen stomach mucosal damage (Devi et al. 2007; Crowe and Kinsey 2017). LAB further produced a considerable decrement in LPO and MDA amounts while boosting the SOD and CAT activities. These outcomes are in line with Liu et al. (2006) and Wang et al. (2018), who found that LAB increases activities of endogenous antioxidative enzymes in liver and kidney damage models (Liu et al. 2006; Wang et al. 2018). The mechanism by which LAB mediates its NLRC3-protective action is by stimulating Nrf2/HO-1 signaling, as previously stated (Wang et al. 2015). By activating Nrf2, LAB could promote redox balance and lipid peroxidation level in gastric tissues. Furthermore, the 0 2 4 6 8 10 12 14 controlind.LAB Eso. Ulcer score a c b c Figure 5. Effect of LAB on ulcer score in diclofenac-induced gastric ulcer in treated groups. Outcomes were reflected as M ± SEM. Different lowercase letters represent substantial differences among groups. A p-value < 0.05 is regarded as a substantial difference. Figure 6. Histological sections of gastric tissue processed with hematoxylin and eosin (H&E) and visualized under ×100 magnification. A. Shows normal gastric architecture in the control group; B. Displays desquamation of approximately two-thirds of the stomach mucosal layer (black arrow), along with submucosal edema (blue arrow) and vascular congestion in the induction group; C. Illustrates mild hyperemia (blue arrow) and blood vessel congestion (black arrow) in the group treated with salvianolic acid B; D. Reveals mild hyperemia (blue arrow) in the group treated with esomeprazole. Pharmacia 72: 1–11 7 phenolic hydroxyl group in its compound structure makes LAB bind with superoxide anions, suppressing the chain of lipid-oxidation reactions (Zhao et al. 2008). Notably, the antioxidant performance of LAB in the present study was similar to that of esomeprazole, which indicates that its cytoprotective effect may be mediated beyond acid-inhibitory action. Unlike proton pump inhibitors exerting their action mainly by inhibition of gastric acid secretion (Mullin et al. 2009), LAB protects the stomach by combating ROS and safeguarding mitochondria. This double antioxidant and cytoprotective activity might give improved mucosal barriers (Chen et al. 2023), including those required during long-term NSAID therapy. Modulation of inflammation-associated cytokines Increased output of inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, contributes to the development of cologastric ulceration via causing mucosal inflammation and epithelial degeneration (Musumba et al. 2009; Jaafar et al. 2025). Meanwhile, minimized concentrations of IL10 deepen the inflammatory reactions (Manna et al. 2017; Mohammed et al. 2025). NSAIDs remarkably increased IL-6 in the gastric tissue and decreased IL-10 within stomach tissues, suggesting an inflammation stage. These findings are consistent with those described by Goswami et al. (2017), who reported an increment in the level of IL-6 and TNF-α that may cause leukocyte infiltration along with mucosal necrosis, which is responsible for the pathogenesis of NSAID-evoked gastric ulceration (Goswami et al. 2017). IL-6 is a multifaceted cytokine increasing vascular permeability and inducing neutrophil migration to the site of injury, resulting in profound tissue damage (Danisman et al. 2023; Shareef et al. 2025; Tariq et al. 2025). However, IL-10 is a robust anti-inflammatory protein that hampers NF-κB signaling and restricts the generation of chemotactic cytokines (Zhou et al. 2024; Abbas et al. 2025; Attarbashee et al. 2025). Decreased IL-10 production in the presence of NSAIDs indicates impairment of anti-inflammatory control (Abdul-Majeed et al. 2025; Sharif et al. 2025). LAB treatment could partially reverse these cytokine changes via significant reduction of IL-6 and increase of IL-10 production. This aligns with Zou et al. (2022), who also reported that LAB inhibited the production of IL-6 and TNF-α in macrophages and had M2 anti-inflammatory polarization (Zou et al. 2022). Likewise, IL-10 generation was boosted by LAB during high-fat-diet-driven inflammation, offering a systemic immunomodulatory advantage (Wang et al. 2017). Mechanistically, LAB has been found to regulate transcriptional activity of inflammation-related cytokines by suppression of both NF-κB and MAPK signaling (Zhang et al. 2018). Through inhibiting IκBα phosphorylation and NF-κB nuclear translocation, LAB downregulates the expression of one cytokine (IL-6) while upregulating that of another (IL-10), possibly through activation of STAT3 and PPARγ pathways (Zhang et al. 2022). The present findings suggest that LAB’s anti-inflammatory action extends beyond antioxidant capacity and directly impacts molecular interactions implicated in cytokine balance and immunological homeostasis in stomach tissue. Angiogenic/growth factor endpoints VEGF and HGF are principal angiogenic regulators that promote endothelial proliferation and new capillary formation, all essential to re-establish blood flow while also stimulating epithelial regeneration, securing effective wound and ulcer healing (Bamba et al. 1998; Thammer et al. 2025). VEGF and HGF were considerably reduced by diclofenac in the present work, confirming the work of Manzano-Moreno et al. (2018), who found VEGF transcription in osteoblastic cultures was inhibited via diclofenac (Manzano-Moreno et al. 2018), owing to downregulated prostaglandin formation, which is implicated in tissue healing and angiogenesis (Bamba et al. 1998). LAB greatly increased VEGF and HGF expression, suggesting promotion of mucosal regeneration. Li et al. (2020) demonstrated that LAB activates VEGF-induced angiogenesis through the PI3K/Akt and ERK1/2 pathways, resulting in endothelial proliferation and capillary formation (Li et al. 2020). In the same vein, the roles of HGF and c-Met through epithelial restoration and ulcer healing were observed (Ha et al. 2017). Through these growth factors upregulation, LAB might also induce angiogenesis and re-epithelialization, which would be a structural support for the histological improvement (Hu et al. 2025). This pro-angiogenic effect distinguishes LAB not only from classic acid-suppressing medications but also indicates that its healing effects also embrace the vascular and regenerative levels. The combined anti-inflammatory, pro-angiogenic, and antioxidative qualities of LAB were examined in an exhaustive layout for safeguarding mucosal tissues. Histopathological correlation and integrated interpretation Histopathological findings were closely matched with the biochemical and molecular observations. Diclofenac caused marked mucosal necrosis, loss of epithelium, submucosal edema, and vascular congestion corresponding to that observed by Devi et al. (2007). On the contrary, LAB could help restore the integrity of mucosa, with a marked decrease in inflammatory cell infiltration and preserved gastric architecture. Comparable protective effects were shown by Govindarasu et al. (2021) in colitis, where LAB reduced epithelial erosion and inflammation-induced damage (Govindarasu et al. 2021). The combination of biochemical normalization (MDA, IL-6 decrease, and SOD, CAT, and IL-10 increase) and increased expression of VEGF/HGF, along with histological restoration, further confirmed that LAB’s gastroprotection is multifactorial. It probably includes early reduction in oxidative damage, followed by inhibition of inflammation, and finally an increase in mucosal repair. Jaafar FR et al.: Lithospermic acid B mitigates rat model of NSAIDs-induced gastric injury8 This time-dependent process appears to be part of an integrated cytoprotective program as opposed to a primary antioxidant effect. Study limitations This study has some limitations that need to be acknowledged. First, an animal model may not be sufficient to accurately mimic the complex pathophysiological process of human NSAID-induced stomach damage. Secondly, we found that we did not measure the molecular signaling networks involving Nrf2, NF-κB, and PI3K/Akt. Thirdly, the pharmacokinetics and dosage responses of LAB were not studied. The roles of signaling pathways to be assessed via western blotting or immunohistochemistry, the impact of different dosing regimens, and any clinical or translational implications require further exploration. Conclusion The outcomes of the present work demonstrated that lithospermic acid B could be a promising candidate for NSAID-aggravated gastric mucosal injury. Its distinctive profile of antioxidative, anti-inflammatory, and angiogenic effects contributes to enhanced gastric ulcer healing and renders it a natural substitute for traditional therapies. Clinically, these findings imply that LAB may be an adjunct or even a standalone therapy in patients at risk for NSAID-induced gastric injury. Next studies ought to concentrate on dose adjustments, prolonged safety evaluations, and clinical testing to demonstrate the effectiveness of LAB in humans. Acknowledgments The authors are heartily thankful to the College of Medicine, Department of Pharmacology at Al-Nahrain University; the High Institute for Infertility Diagnosis and Assisted Reproductive Technologies at Al-Nahrain University; the College of Pharmacy at Dijlah University; and the College of Pharmacy at Al-Mustaqbal University, which offered the space and equipment needed to successfully accomplish this work. Additional information Conflict of interest The authors have declared that no competing interests exist. Ethical statements The authors declared that no clinical trials were used in the present study. The authors declared that no experiments on humans or human tissues were performed for the present study. The authors declared that no informed consent was obtained from the humans, donors or donors’ representatives participating in the study. Experiments on animals: The Institutional Review Board (IRB) gave ethical clearance to the study on October 9, 2023, under approval number IRB/47/UNCOMIRB20250447. The authors declared that no commercially available immortalised human and animal cell lines were used in the present study. Use of AI No use of AI was reported. Funding This research obtained no funds. Author contributions Farrah Rasool Jaafar played a significant role in the study design, especially through planning of the experimental protocol and following up on the laboratory procedures; her expertise was instrumental in achieving proper methodology performance and trustworthy data. Ali Jihad Hemid Al-Athari contributed to the materials collecting portion, conducting histological and biochemical assays. Muayad Sraibet Abbood participated in the results interpretation, paper revisions, and statistical evaluations. Their contributions meet the ICMJE criteria for authorship. Their contributions fully meet the ICMJE criteria for authorship. Hayder Ridha-Salman assisted in methodological design, organized and analyzed the data, and prepared the final copy of the manuscript. Haitham Mahmood Kadhim contributed to the development of the methodology, carried out statistical analyses, and managed data coding. Author ORCIDs Farrah Rasool Jaafar https://orcid.org/0009-0002-2206-4868 Ali Jihad Hemid Al-Athari https://orcid.org/0000-0003-2530293X Muayad Sraibet Abbood https://orcid.org/0000-0002-0262-3813 Hayder Ridha-Salman https://orcid.org/0000-0003-1594-4883 Haitham Mahmood Kadhim https://orcid.org/0000-0001-80972560 Data availability Data that validate the results of this research article are obtainable from the corresponding author upon appropriate request. References Abbas AH, Abbood MS, Ridha-Salman H, Fakhri SA, Abbas ZH, Al-Athari AJH (2025) Suppressive effect of topical moxifloxacin on imiquimod-induced model of psoriasis in mice. Naunyn-Schmiedeberg’s Archives of Pharmacology. https://doi.org/10.1007/s00210-025-04317-2 Abbod MS, Al-Jawad FH, Anoze AA, Jawad MA, Qasim BJ (2014) Antiatherosclerotic Effect of L-thyroxine and Verapamil Combination on Thoracic Aorta of Hyperlipidemic Rabbits. International Journal of Pharmaceutical Sciences Review and Research 27(1): 254–260. 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