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Empagliflozin Inhibits Cadmium-Induced Hepatic Cell Apoptosis Through Endoplasmic Reticulum Stress and Autophagy
Naeem F Qusty1, Bayan T Bokhari1, Medhat Taha2,3
1Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al‒Qura University, Makkah, 21955, Saudi Arabia.
Abstract:
Cadmium (Cd), a well-known toxic heavy metal, adversely affects multiple organs. The SGLT-2 inhibitor empagliflozin (EMPA) exhibits significant antioxidant properties and hypoglycemic potential. This study aimed to investigate the hepatoprotective effect of EMPA against Cd-induced liver injury and elucidate its molecular mechanisms. Thirty-two male rats were allocated into four groups of eight rats each: group I (control group), group II (EMPA group), group III (Cd group), and group IV (Cd + EMPA group). Cd intake disrupted liver enzymes (ALT, AST, and ALP) and impaired hepatic histological architecture. Cd induced hepatic oxidative stress, as evidenced by increased MDA levels and reduced antioxidant enzymes, including SOD, GPx, and CAT. It downregulated the Nrf2/HO-1 pathway and elevated proinflammatory mediators IL-1β, IL-6, and TNF-α. Furthermore, Cd increased ER stress markers GRP78 and CHOP, along with apoptotic markers Bax and caspase-3 while decreasing anti-apoptotic Bcl-2 and reducing the autophagic indicator Beclin-1. Interestingly, EMPA administration in the Cd + EMPA group attenuated Cd-induced hepatic deterioration, improving hepatocyte structure. This beneficial effect was driven by the downregulation of hepatic oxidative stress, inflammation, ER stress, and apoptosis, alongside the upregulation of the autophagy process. In conclusion, this study highlights the hepatoprotective effect of EMPA against Cd-induced liver injury, elucidating its underlying molecular mechanisms.
Insights
Empagliflozin (EMPA) protects the liver from cadmium (Cd) toxicity by reducing oxidative stress, inflammation, and apoptosis. This SGLT-2 inhibitor promotes autophagy, offering a potential therapeutic strategy for heavy metal-induced liver injury.
Area of Science:
- Toxicology
- Pharmacology
- Hepatology
Background:
- Cadmium (Cd) is a toxic heavy metal causing multi-organ damage, particularly the liver.
- Empagliflozin (EMPA), an SGLT-2 inhibitor, possesses antioxidant and anti-inflammatory properties.
Purpose of the Study:
- To investigate the hepatoprotective effects of empagliflozin against cadmium-induced liver injury.
- To elucidate the molecular mechanisms underlying empagliflozin's protective action.
Main Methods:
- Male rats were divided into control, empagliflozin, cadmium, and cadmium + empagliflozin groups.
- Assessed liver enzymes, histological architecture, oxidative stress markers, inflammatory mediators, ER stress, apoptosis, and autophagy.
Main Results:
- Cadmium exposure elevated liver enzymes, induced oxidative stress, inflammation, ER stress, and apoptosis, while suppressing antioxidant enzymes and autophagy.
- Empagliflozin treatment attenuated cadmium-induced liver damage, reduced oxidative stress, inflammation, ER stress, and apoptosis, and enhanced autophagy.
Conclusions:
- Empagliflozin demonstrates significant hepatoprotective effects against cadmium-induced liver injury.
- The protective mechanisms involve mitigating oxidative stress, inflammation, ER stress, and apoptosis, and promoting autophagy.
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