Dexamethasone (DEX) is a potent synthetic glucocorticoid widely used for its anti-inflammatory and immunosuppressive properties. It is frequently prescribed in the management of various medical conditions such as asthma, severe allergies, autoimmune disorders, and various malignancies (Madamsetty et al., 2022; Caramori, 2019). Glucocorticoids, including dexamethasone, are also integral in treating inflammation, inflammatory bowel diseases, allergic reactions, and exacerbations of chronic respiratory diseases like asthma (Reichardt et al., 2021). Furthermore, corticosteroids effectively manage acute respiratory distress syndrome (ARDS) (Chang et al., 2022).

Despite their clinical utility, prolonged use of glucocorticoids is associated with significant adverse effects. Dexamethasone, in particular, has been linked to metabolic disturbances such as hyperglycemia, insulin resistance, hepatic steatosis, and the development of type II diabetes (Madamsetty et al., 2022). Additionally, extended dexamethasone exposure has been shown to induce degenerative necrosis and inflammatory changes in hepatic tissues in experimental models (Ahmad, 2024).

Given the toxicity associated with prolonged glucocorticoid use, there is a growing interest in exploring dietary and botanical interventions to mitigate these adverse effects. Botanical drugs with antioxidant and anti-inflammatory properties are increasingly investigated as adjunctive therapies in metabolic and hepatic disorders. Spirulina platensis, a blue-green microalga classified as a botanical drug, has garnered attention due to its diverse pharmacological activities. It exhibits a unique spiral morphology and thrives in extreme environmental conditions. The species most commonly utilized in dietary and therapeutic applications are Spirulina maxima and Spirulina platensis (Althobaiti et al., 2024).

Spirulina platensis contains 65%–71% protein by dry weight, including 47% essential amino acids such as methionine. It also provides 15%–25% carbohydrates, 8%–13% minerals, 3%–7% lipids, and 8%–10% fiber. Moreover, it is a rich source of chlorophyll, phycocyanin, carotenoids, vitamins, and various bioactive metabolites (Iyer, 2011). Siva Kiran et al. (2015) showed that the blue-green algae extract Spirulina platensis is used worldwide as a meal and botanical drug. It is a healthy botanical drug with amino acids, lipids, vitamins, minerals, and antioxidants. A recent study has connected Spirulina platensis to immunomodulatory, pro-inflammatory, antioxidant, anti-cancer, and antiviral effects in animal models and humans. Hypolipidemic, hypoglycemic, and hypotensive effects are emerging, as are other health benefits, although hepatic consequences are poorly studied (Reboleira, 2019). Spirulina platensis possesses a substantial concentration of macro and micronutrients, necessary amino acids, proteins, lipids, vitamins, minerals, and antioxidants. It has a considerable vitamin B12 concentration and is an excellent source of beta-carotene, iron, calcium, and phosphorus. One gram of spirulina protein is equivalent to one pound of assorted vegetables. Spirulina enhances various human health parameters, from addressing malnutrition to providing antioxidant metabolites (Sonawane et al., 2023). This study was designed to evaluate the hepatoprotective potential of Spirulina platensis aqueous extract (SPAE) against DEX-induced oxidative stress, apoptosis, lipid disturbances, and transcriptional dysregulation in male rats. The underlying mechanisms, including modulation of redox-sensitive signaling pathways (e.g., Nrf2, AMPK) and apoptotic regulators (Bax, Bcl-2, p53), were also investigated.

For pure glucocorticoid action, the synthetic glucocorticoid dexamethasone (DEX) outperforms natural cortisol and corticosterone (Abd El-Hakam et al., 2022). Both males and females treated with DEX developed glucose and lipid intolerance, elevated levels of plasma insulin and triacylglycerol, increased amounts of glycogen and fat in the liver, and increased mass of islets in the pancreas (da Silva et al., 2023). Finding alternative remedies that are both safe and natural is, thus, a top priority. This work examined how SPAE protected rats’ livers from DEX-induced hyperlipidemia and injury.

In this study, administering dexamethasone (DEX) at a dose of 10 μg/kg/day for 4 weeks led to a noticeable suppression of food intake (FI) and a decline in body weight gain (BWG) in rats. This effect is likely associated with a dose-dependent rise in plasma leptin levels triggered by DEX, possibly contributing to reduced appetite and weight gain. Furthermore, it is proposed that leptin might be more involved in elevating energy expenditure rather than merely decreasing food consumption in DEX-induced anorexia (Won Jahng et al., 2008). This result was consistent with many reports indicating that DEX substantially reduced weight and increased fat mass (Li et al., 2017; Koorneef et al., 2022). Conversely, SPAE exhibited notable increases in feed intake (FI) and body weight gain (BWG) relative to the DEX group. The nutritional application of Spirulina platensis may enhance production performance, perhaps due to the high nutritional value of diets supplemented with Spirulina (Nassar et al., 2023; Cho et al., 2020; Aissaoui et al., 2017).

The positive effects on production performance may be due to the nutritional value of diets supplemented with Spirulina platensis, which is known for its high nutrient content (Kritsch et al., 2002; Wego et al., 2019). Moreover, Jiao et al. (2020) found that DEX considerably caused a swollen liver, medically known as hepatomegaly. They imply that lipid buildup could be associated with DEX-induced hepatomegaly. In contrast to the placebo group, SPAE reduces liver weight.

This data agrees with Hussein et al. (2020), who investigated the anti-obesity impact of SPAE in high-fat diet-induced obese rats. Also, Coué et al. (2019) exhibited that spirulina liquid extract alleviated western diet-induced non-alcoholic steatohepatitis, evidenced by a lower ratio of liver weight to body weight.

Dyslipidemia caused by DEX is associated with increased ROS and oxidative injury (Mohammed, 2021). Consistent with what Arab Dolatabadi and Mahboubi found, the present study found that injecting DEX considerably raised TC, TG, LDL, and VLDL while lowering HDL associated with the negative control group (Arab Dolatabadi and Mahboubi, 2015). One possible explanation for the observed shift from HDL to LDL following DEX treatment is increased hepatic lipogenesis due to increased fatty acid synthase and acetyl-CoA carboxylase expression (Cai et al., 2011). Rats administered SPAE improved lipid profiles in rats injected with DEX. Our data are supported by Hussein et al. (2020). The aqueous extract of SPAE dramatically reduced serum levels of total cholesterol, triacylglycerol, and LD. This lipid-lowering effect is likely linked to antioxidant-rich metabolites such as phycocyanin and phenolic acids, which may prevent fatty acid oxidation and lipolysis. Additionally, the polyunsaturated fatty acids in SPAE contribute to its anti-obesity properties. The extract’s essential fatty acids also help inhibit fat and cholesterol buildup. Similar outcomes were reported by Ouédraogo (2020). Researchers found that spirulina can lower lipid levels due to its high concentration of omega-3 and omega-6 fatty acids, beta-carotene, alpha-tocopherol, phycocyanin, phenols, and several minerals. There was a substantial elevation in liver enzyme activities in rats injected with DEX. These results are following Hasona and Morsi (2019). The results indicated that ALT and AST decreased extensively in the Spirulina group (Mazloomi et al., 2022). Daily supplementation with 1 g of Spirulina platensis for 12 weeks significantly improved lipid profiles in dyslipidaemic Cretan patients, notably reducing triglycerides, LDL-C, total cholesterol, and non-HDL-C levels. These results support the hypolipidaemic potential of Spirulina as a natural, well-tolerated dietary supplement and suggest its usefulness as an adjunct or alternative therapeutic strategy for managing dyslipidaemia, particularly in individuals at risk of cardiovascular disease (Mazokopakis et al., 2014).

GGt, T.BIL, and D.BIL levels were elevated in rats administered DEX. Our results agree with Alkot et al. (2022), confirming that DEX treatment caused a substantial increase in bilirubin levels. Potentially, oxidative stress causes alterations in cell membrane permeability, which alters the effective stress on the membrane, leading to elevated bilirubin levels (Itroutwar et al., 2020). In contrast, serum GGT, T.BIL, and D.BIL parameters significantly decreased in rats with SPAE. In harmony with these findings, Koite et al. (2022) tested the effects of a liquid Spirulina extract on metabolic abnormalities and oxidative stress in individuals suffering from metabolic syndrome.

DEX reduced total protein, albumin, and globulin (Mobeen et al., 2022; Ibrahim et al., 2020). The administration of DEX decreased serum total protein, albumin, and globulin levels (Savary et al., 2001). The decline in TP content can be useful in DEX regarding the severity of hepatocellular damage (Alavian et al., 2014). All groups administered with SPAE showed significant increases in serum proteins associated with the negative control group. The data are consistent with Youssef et al. (2023), who noticed that feeding 10.0% Spirulina substantially boosted the albumin serum level. El-Hashash (2021) reported that diet supplementation introduced to MSG–MSG-administered groups with Spirulina powder (0.5% and 1%) significantly increased total protein, albumin, and globulin. The normalized levels of serum proteins in SPAE contribute to phenolic chemicals in SP (Ramez et al., 2021). In aquatic models, Spirulina platensis enhanced haematological and serum biochemical parameters in rainbow trout (Oncorhynchus mykiss) (Yeganeh et al., 2015) and improved growth, immune response, and intestinal morphology in Nile tilapia (Oreochromis niloticus) (Al-Deriny et al., 2020). While occurring in different tissues and species, these benefits corroborate Spirulina’s consistent biological activity and role in metabolic modulation and immune resilience.

Lipid peroxidation is one of the basic mechanisms of tissue injury caused by free radicals (Mallikarjuna, 2018). In the present investigation, the injection of DEX led to the elevation of (MDA & NO) in the hepatic tissues of rats (Mallikarjuna, 2018). Also, our data are supported by Hasona and Morsi (2019); it was revealed that DEX treatment produced oxidative injury, as evidenced by the increased hepatic lipid peroxidation marker MDA, DEX-induced diminution of SOD and CAT in the hepatic tissue of rats. The reduction in both SOD and CAT activity may be associated with the suppression of enzyme protein production (Mallikarjuna, 2018; Alsadee and Agbashee, 2021). Abou-Seif et al. (2019) demonstrated that excessive levels of DEX significantly diminished overall antioxidant capacity and SOD activity, leading to oxidative stress through increased concentrations of hydrogen peroxide and MDA.

On the other hand, SPAE administration revealed significant decreases in (MDA & NO) and an important improvement in (CAT & SOD). Our findings, in line with previous findings by Al-Qahtani and Binobead (2019), SPAE treatment conferred significant, dose-dependent protection against liver oxidative stress caused by d-galactosamine (d-GalN) in rats, as demonstrated by elevated activity of the antioxidant enzymes SOD and CAT. The protective impact may be associated with the high concentration of antioxidant-rich metabolites in SPAE, such as C-phycocyanin, β-carotene, vital fatty acids, amino acids, vitamins, minerals, proteins, lipids, and carbs. These metabolites are recognized for their potent antioxidant and anti-inflammatory properties (Abdel-Daim et al., 2016). The biological activity of Spirulina platensis has been widely validated across multiple species, supporting its broad-spectrum protective effects. For instance, Zahran and Emam (2018) demonstrated that Spirulina ameliorated nicotine-induced renal oxidative stress and inflammation in rats, aligning with our hepatic findings regarding its anti-inflammatory and antioxidant properties. Similarly, Ardicli et al. (2022) reported modulation of stress-responsive HSP70 gene expression in rat brain tissue, suggesting systemic stress-mitigating effects that support our observed anti-apoptotic activity in the liver. The dietary supplementation with Spirulina platensis and its bioactive metabolites C-phycocyanin significantly improves lifespan and locomotor activity in a Drosophila model of Parkinson’s disease (DJ-1βΔ93). These beneficial effects are associated with modulation of oxidative stress markers and stress-responsive pathways, including HSP70 and JNK signaling. The findings highlight the potential of spirulina as a nutraceutical intervention for managing neurodegenerative disorders such as Parkinson’s disease through its antioxidant and cytoprotective properties (Kumar et al., 2017). These cross-species findings reinforce the mechanistic plausibility of our results and highlight Spirulina platensis as a robust nutraceutical candidate capable of modulating oxidative stress, apoptosis, and lipid metabolism in diverse biological systems.

Dexamethasone induces DNA damage and generates oxidative stress to exert an anti-cancer effect (Motafeghi et al., 2022). These results agree with (Motafeghi et al., 2022), who reported that dexamethasone has an anti-cancer effect by causing DNA damage and inducing oxidative injury. Also, the induction of DNA damage by Dexamethasone agrees with (Baumeister et al., 2009), who indicated that dexamethasone induced slight but considerable DNA fragmentation. Several research studies have reported the protective efficacy of spirulina against dexamethasone genotoxicity. Our results showed that spirulina has an effective role in reducing dexamethasone’s toxicity through reduced DNA damage. The high dose was more effective than the low dose, and both positively reduced DNA damage by reducing DNA tail and DNA moment.

Our results were confirmed by histopathological evaluation. In our results, dexamethasone’s induction of steatosis development agrees with (Hasona et al., 2017; Yin et al., 2017). They observed that an overdose of dexamethasone resulted in hyperglycemia, hyperlipidemia, the development of steatosis, and fatty liver. The present findings concur with (Abou-Seif and Hozayen, 2023); they asserted that dexamethasone precipitated pathological problems, including widespread fatty alteration in the hepatocytes within the hepatic parenchyma. The livers of rats administered DEX exhibited positive caspase-3 expression, which is recognized for its specific function in the ultimate triggering of apoptosis. These findings concur with those who indicated that dexamethasone induces oxidative stress and activates caspase 3, ultimately resulting in hepatotoxicity (Feng et al., 2017), who reported that treatment with Dex caused a remarkable increase in caspase-3 in osteoblasts.

SPAE’s protective effect is likely linked to its rich composition, including βPhycocyanin, selenium, β-carotene, and superoxide dismutase. Phycocyanin’s ability to prevent reactive metabolites and scavenge free radicals protects the liver (Ama Moor et al., 2017). Moreover, Al-Qahtani and Binobead (2019) Spirulina demonstrated a beneficial role in preserving liver function, offering protection against liver damage induced by harmful toxins when included in the diet.

This study explored the protective effects of Spirulina platensis aqueous extract against dexamethasone (DEX)-induced oxidative stress, apoptosis, lipid dysregulation, and DNA damage at the gene expression level. DEX significantly altered the expression of key regulatory genes, while Spirulina co-treatment modulated these alterations in a dose-dependent manner, suggesting its potential as a therapeutic nutraceutical. DEX treatment downregulated Nrf2 and SOD2, reflecting impaired antioxidant defense. Nrf2 is a central transcription factor that activates cellular antioxidant genes via the Keap1–Nrf2–ARE signalling pathway (Kensler et al., 2007). The restoration and upregulation of Nrf2 and SOD2 by Spirulina, particularly at 800 mg/kg, suggest activation of antioxidant responses. These effects are likely attributed to Spirulina’s rich composition of phycocyanin, β-carotene, and polyphenols, known to counteract oxidative stress (Ibrahim et al., 2018). DEX significantly increased hepatic Keap1 expression, an established inhibitor of Nrf2, which restricts antioxidant gene transcription by sequestering Nrf2 in the cytoplasm and promoting its degradation (Taguchi et al., 2011). SPAE treatment attenuated Keap1 expression, implying the release and nuclear translocation of Nrf2, thereby enhancing endogenous antioxidant defences. This mechanism is consistent with prior findings where Spirulina-derived metabolites promoted Nrf2 activation and reduced oxidative stress in hepatic injury models (Sibiya et al., 2022). Concurrently, SPAE upregulated AMPK expression, which was suppressed by DEX administration. AMPK is central to energy regulation, lipid oxidation, and inflammation control (Hardie, 2014). The observed AMPK upregulation aligns with studies showing that Spirulina platensis and its phycocyanin content can activate AMPK pathways, improving lipid metabolism and redox balance (Karimzadeh et al., 2025).

The therapeutic effects of Spirulina have been attributed to its rich content of bioactive metabolites, including phycocyanin, β-carotene, and phenolic acids, which exhibit strong antioxidant, anti-inflammatory, and lipid-lowering properties (Khan et al., 2005). These metabolites likely contributed to the modulation of Keap1 and AMPK pathways observed in our study.

Apoptosis markers were also significantly influenced by DEX. The upregulation of Bax and suppression of Bcl-2 in the DEX group indicate a shift toward pro-apoptotic signalling. The Bax/Bcl-2 ratio is a well-known indicator of apoptotic activity, and its normalization by Spirulina supports its anti-apoptotic capacity. These findings are consistent with previous research showing Spirulina’s inhibition of apoptosis in chemically induced hepatotoxicity (Amer et al., 2023). DEX-induced suppression of PPAR-α further suggests disrupted lipid metabolism. PPAR-α is critical in regulating fatty acid oxidation and maintaining lipid homeostasis (Desvergne et al., 2006). Spirulina’s ability to restore and enhance PPAR-α expression demonstrates its lipid-modulating potential, aligning with observed improvements in serum lipid profiles in related studies. Finally, p53 was significantly upregulated following DEX exposure, indicating increased cellular stress and DNA damage. As a tumour suppressor and regulator of cell cycle arrest and apoptosis, p53 activation follows oxidative or genotoxic insults (Vousden and Lane, 2007). Spirulina co-treatment significantly reduced p53 expression, suggesting DNA damage and cellular stress mitigation. These findings highlight the protective, multi-targeted effect of Spirulina platensis against glucocorticoid-induced molecular damage. Modifying gene expression across antioxidant, apoptotic, metabolic, and genomic stress pathways reinforces its promise as a natural therapeutic agent.

While the 28-day treatment period and use of only male rats were consistent with standard protocols to reduce variability in early-phase toxicological studies, these choices limit the extrapolation of our findings to chronic exposure scenarios and across sexes. Future studies should adopt longer treatment durations and include both male and female animals to assess the sustained effects and potential sex-specific responses to Spirulina platensis. Additionally, although we observed significant modulation of Nrf2, PPAR-α, and p53 gene expression, our study does not establish direct causality. Mechanistic confirmation using pathway-specific inhibitors or genetic models will be essential in future work to delineate the specific molecular targets underlying SPAE’s protective actions. Although the Spirulina platensis powder was obtained from a reputable supplier and analyzed by HPLC, the extract lacked standardization to a specific bioactive marker. Future studies should standardize key metabolites like phycocyanin or total phenolics to enhance reproducibility and pharmacological consistency. Although alterations in Bax, Bcl-2, and caspase-3 expression strongly indicate activation of the intrinsic apoptotic pathway, mitochondrial integrity or membrane potential (ΔΨm) was not directly assessed in this study. Future investigations are warranted to confirm these findings using mitochondrial-specific assays to elucidate further the mechanisms by which Spirulina platensis mitigates DEX-induced hepatotoxicity.

The antioxidant effects of Spirulina platensis aqueous extract (SPAE) contributed to regulating biochemical parameters, including liver enzymes and lipid profiles, in male rats subjected to dexamethasone-induced oxidative stress. Additionally, SPAE modulated the expression of key genes involved in oxidative stress response (Nrf2, SOD2), apoptosis (Bax, Bcl-2), lipid metabolism (PPAR-α), and DNA damage (p53), further supporting its protective role at the molecular level. These findings highlight the potential of SPAE as a functional metabolite in food and beverage formulations aimed at enhancing antioxidant defences and mitigating glucocorticoid-induced metabolic disturbances. Further research is warranted to validate its efficacy and safety for human consumption.