Linagliptin, a DPP‐4 inhibitor, activates AMPK/FOXO3a and suppresses NFκB to mitigate the debilitating effects of diethylnitrosamine exposure in rat liver: Novel mechanistic insights

Accumulating evidence suggests that dysregulation of FOXO3a plays a significant role in the progression of various malignancies, including hepatocellular carcinoma (HCC). FOXO3a inactivation, driven by oncogenic stimuli, can lead to abnormal cell growth, suppression of apoptosis, and resistance to a...

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Published in:The FASEB journal 2024-02, Vol.38 (4), p.e23480-n/a
Main Authors: Abdelhady, Rasha, Mohammed, Osama A., Doghish, Ahmed S., Hamad, Rabab S., Abdel‐Reheim, Mustafa Ahmed, Alamri, Mohannad Mohammad S., Alharthi, Muffarah Hamid, Alfaifi, Jaber, Adam, Masoud I. E., Alhalafi, Abdullah Hassan, Mohammed, Nahid A., Isa, Adamu Imam, Abdel‐Ghany, Sameh, Attia, Mohammed A., Elmorsy, Elsayed A., AL‐Noshokaty, Tohada M., Nomier, Yousra, El‐Dakroury, Walaa A., Saber, Sameh
Format: Article
Language:English
Subjects:
AMP-Activated Protein Kinases
AMPK
Animals
Anti-Inflammatory Agents
Antiviral Agents
Carcinoma, Hepatocellular - chemically induced
Carcinoma, Hepatocellular - drug therapy
diethylnitrosamine
Diethylnitrosamine - toxicity
Dipeptidyl-Peptidase IV Inhibitors
FOXO3a
Hypoglycemic Agents
Linagliptin
Linagliptin - pharmacology
liver damage
Liver Neoplasms - chemically induced
Liver Neoplasms - drug therapy
NFκB
Protease Inhibitors
Rats
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Summary:Accumulating evidence suggests that dysregulation of FOXO3a plays a significant role in the progression of various malignancies, including hepatocellular carcinoma (HCC). FOXO3a inactivation, driven by oncogenic stimuli, can lead to abnormal cell growth, suppression of apoptosis, and resistance to anticancer drugs. Therefore, FOXO3a emerges as a potential molecular target for the development of innovative treatments in the era of oncology. Linagliptin (LNGTN), a DPP‐4 inhibitor known for its safe profile, has exhibited noteworthy anti‐inflammatory and anti‐oxidative properties in previous in vivo studies. Several potential molecular mechanisms have been proposed to explain these effects. However, the capacity of LNGTN to activate FOXO3a through AMPK activation has not been investigated. In our investigation, we examined the potential repurposing of LNGTN as a hepatoprotective agent against diethylnitrosamine (DENA) intoxication. Additionally, we assessed LNGTN's impact on apoptosis and autophagy. Following a 10‐week administration of DENA, the liver underwent damage marked by inflammation and early neoplastic alterations. Our study presents the first experimental evidence demonstrating that LNGTN can reinstate the aberrantly regulated FOXO3a activity by elevating the nuclear fraction of FOXO3a in comparison to the cytosolic fraction, subsequent to AMPK activation. Moreover, noteworthy inactivation of NFκB induced by LNGTN was observed. These effects culminated in the initiation of apoptosis, the activation of autophagy, and the manifestation of anti‐inflammatory, antiproliferative, and antiangiogenic outcomes. These effects were concomitant with improved liver function and microstructure. In conclusion, our findings open new avenues for the development of novel therapeutic strategies targeting the AMPK/FOXO3a signaling pathway in the management of chronic liver damage. Graphical representation of the mechanism of Linagliptin (LNGTN) in suppressing hepatocellular carcinoma (HCC) progression. LNGTN may inhibit early HCC neoplastic events by raising FOXO3a nuclear vs. cytosolic fraction. FOXO3a activation may induce apoptosis, autophagy, and angiogenesis inhibition.
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.202302461RR