Melatonergic Modulation of SIRT1-Nrf2 Signaling Protects Against Doxorubicin-Induced Hepatic Injury in Rats

Q: What are the key findings of this study?

Melatonin and agomelatine significantly reduced hepatic 99mTc-PYP scintigraphic uptake (p=0.0014 and p<0.001) and serum liver enzymes while restoring SIRT1 and Nrf2 levels against doxorubicin injury.

Q: What is the clinical evidence from this study?

Population: Doxorubicin-induced hepatic injury (n=28). Intervention: Melatonin or Agomelatine vs. Doxorubicin alone (cumulative dose 18 mg/kg i.p. over days 5, 6, and 7) and saline control (1 mL/kg i.p. once daily). Primary outcome: Hepatic 99mTc-pyrophosphate (99mTc-PYP) scintigraphic uptake and serum liver enzymes (AST, ALT, LDH) (p=0.0014 for melatonin; <0.001 for agomelatine vs DOX).

Q: What does this research mean for the field?

Melatonin and agomelatine protect against doxorubicin-induced hepatic injury by reducing oxidative stress and inflammation and restoring SIRT1 and Nrf2 signaling. Novelty: ClaimNovelty.CONFIRMATORY. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

Investigate the potential hepatoprotective effects and molecular mechanisms of melatonin and agomelatine against doxorubicin-induced liver injury in a rat model.

Haluk Kerim Karakullukçu; Hatice Aygün; Murat Kalın; Mina Karakullukcu; Aylin Arslan; Serdar Şavaş Gül; Ömer Faruk Özkan; Gülçin Ercan

doi:10.3390/biomedicines14071468

June 28, 2026BiomedicinesOpen Access

Melatonergic Modulation of SIRT1-Nrf2 Signaling Protects Against Doxorubicin-Induced Hepatic Injury in Rats

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Key result

Melatonin and agomelatine attenuate doxorubicin-induced liver injury, reducing hepatic 99mTc-PYP uptake and enzyme levels.

P=0.0014 for melatonin; <0.001 for agomelatine vs DOX
n=28

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Why the study?

Doxorubicin use is limited by hepatotoxicity linked to oxidative stress and inflammation, prompting investigation into whether melatonin and agomelatine confer hepatoprotection.

Does pretreatment with melatonin or agomelatine attenuate hepatic necrosis, oxidative stress, and inflammatory signaling in a rat model of doxorubicin-induced hepatotoxicity?

Key Points

Investigate the potential hepatoprotective effects and molecular mechanisms of melatonin and agomelatine against doxorubicin-induced liver injury in a rat model.
Randomized 28 rats into four equal groups: Control, DOX, DOX + Melatonin, and DOX + Agomelatine.
Administered melatonin or agomelatine as a one-week pretreatment prior to doxorubicin injections totaling 18 mg/kg.
Assessed hepatic damage using 99mTc-PYP scintigraphic uptake, serum enzymes (AST, ALT, LDH), oxidative stress markers (MDA, GSH, Nrf2, SIRT1), and inflammatory cytokines (TNF-α, IL-6, IL-10).
DOX alone increased hepatic 99mTc-PYP uptake (p < 0.001) and elevated serum AST, ALT, and LDH (all p < 0.001), whereas co-administration of melatonin or agomelatine significantly reduced radiotracer uptake (p = 0.0014 and p < 0.001, respectively) and lowered AST, ALT, and LDH levels (all p < 0.05).
DOX significantly reduced hepatic SIRT1 (p = 0.002), Nrf2 (p < 0.001), and GSH (p < 0.001) while increasing MDA (p = 0.002); melatonin and agomelatine significantly reversed these alterations, increasing SIRT1 (melatonin: p = 0.009; agomelatine: p = 0.018) and reducing MDA (p = 0.002 for both).
Hepatic TNF-α and IL-6 levels were significantly increased by DOX (p < 0.001) and decreased by melatonin (p < 0.001 and p = 0.0045) and agomelatine (both p < 0.001), while IL-10 was significantly restored by both treatments (melatonin: p = 0.0100; agomelatine: p = 0.0011).

Structured PICO

Does pretreatment with melatonin or agomelatine attenuate hepatic necrosis, oxidative stress, and inflammatory signaling in a rat model of doxorubicin-induced hepatotoxicity?

P

Population

28 adult male Wistar rats (220-280 g) in an experimental model of acute/subacute doxorubicin-induced hepatotoxicity over a 7-day protocol.

I

Intervention

Melatonin 40 mg/kg intraperitoneally once daily for 7 days, or agomelatine 40 mg/kg intraperitoneally once daily for 7 days, administered as a preconditioning and co-treatment regimen with doxorubicin (cumulative dose 18 mg/kg intraperitoneally on days 5, 6, and 7).

C

Comparator

Doxorubicin alone (cumulative dose 18 mg/kg intraperitoneally over three consecutive days) and vehicle control (intraperitoneal saline 1 mL/kg body weight once daily for 7 days).

O

Outcome

Hepatic injury assessed by in vivo 99mTc-pyrophosphate (99mTc-PYP) static scintigraphic uptake (60 minutes post-injection) and serum liver enzyme levels (AST, ALT, and LDH) at day 7.surrogate

Main Result

p-value: p=0.0014 for melatonin; <0.001 for agomelatine vs DOX

Limitations

H&E histopathology and immunohistochemical confirmation were not performed, limiting direct morphological correlation.
Apoptosis-related markers such as caspase-3, Bax, Bcl-2, and TUNEL staining were not evaluated.
Mechanistic experiments (e.g., EX-527 administration, gene silencing, nuclear translocation analysis, co-immunoprecipitation) were not performed, making the SIRT1-Nrf2 relationship associative rather than causal.
Conducted in an acute/subacute non-tumor-bearing rat model, unable to determine effects on antitumor efficacy or long-term chemotherapy protocols.
Lack of H&E histopathology and immunohistochemical confirmation for direct morphological correlation
Absence of direct evaluation of apoptosis-related markers such as caspase-3, Bax, Bcl-2, and TUNEL staining
Lack of mechanistic pathway inhibition or gene-silencing experiments (e.g., EX-527, nuclear translocation, co-immunoprecipitation) to establish a causal link between SIRT1 and Nrf2
Use of an acute/subacute non-tumor-bearing animal model rather than a long-term tumor-bearing chemotherapy model

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Implication

Preconditioning with melatonin or agomelatine protects against acute doxorubicin-induced hepatotoxicity in rats by restoring hepatic SIRT1-Nrf2 antioxidant defenses and suppressing inflammatory cytokines, with 99mTc-PYP scintigraphy serving as a functional marker of hepatic necrosis.

Abstract

Objectives: Doxorubicin (DOX) is an effective chemotherapeutic agent, but its clinical use is limited by hepatotoxicity associated with oxidative stress and inflammatory signaling. This study aimed to investigate the potential protective effects of melatonin and agomelatine on DOX-induced hepatic injury using scintigraphic, biochemical, and molecular parameters. Methods: Twenty-eight rats were randomly divided into four groups: Control, DOX, DOX + Melatonin, and DOX + Agomelatine. Melatonin and agomelatine were administered as a one-week pretreatment, and DOX was injected during the experimental period (total dose: 18 mg/kg). Hepatic injury was evaluated using 99mTc-PYP scintigraphic imaging, serum liver enzymes (AST, ALT, and LDH), oxidative stress markers (MDA, GSH, Nrf2, and SIRT1), and inflammatory cytokines (TNF-α, IL-6, and IL-10). Results: DOX administration significantly increased hepatic 99mTc-PYP uptake, as well as serum AST, ALT, and LDH levels, indicating hepatocellular necrosis and membrane damage. DOX also increased MDA, TNF-α, and IL-6 levels while reducing GSH, Nrf2, SIRT1, and IL-10, demonstrating pronounced oxidative stress and inflammatory activation. Treatment with melatonin or agomelatine significantly reduced tracer uptake and liver enzyme levels compared with the DOX group. Both treatments improved antioxidant status by decreasing MDA and restoring GSH, Nrf2, and SIRT1 levels, while simultaneously attenuating inflammatory cytokine responses through reduction in TNF-α and IL-6 and partial restoration of IL-10. Conclusions: Melatonin and agomelatine attenuated DOX-induced hepatotoxicity by reducing oxidative stress, modulating inflammatory responses, and restoring hepatic SIRT1 and Nrf2 levels. These findings suggest that melatonergic interventions may represent promising protective strategies against doxorubicin-induced liver injury.

Discussion

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Cite This Study

Karakullukçu et al. (2026) studied Doxorubicin-induced hepatic injury (n=28). Melatonin or Agomelatine vs. Doxorubicin alone (cumulative dose 18 mg/kg i.p. over days 5, 6, and 7) and saline control (1 mL/kg i.p. once daily) was evaluated on Hepatic 99mTc-pyrophosphate (99mTc-PYP) scintigraphic uptake and serum liver enzymes (AST, ALT, LDH) (p=0.0014 for melatonin; <0.001 for agomelatine vs DOX). Melatonin and agomelatine significantly reduced hepatic 99mTc-PYP scintigraphic uptake (p=0.0014 and p<0.001) and serum liver enzymes while restoring SIRT1 and Nrf2 levels against doxorubicin injury.

synapsesocial.com/papers/6a435c08759b888809a529d9 https://doi.org/10.3390/biomedicines14071468

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Melatonergic Modulation of SIRT1-Nrf2 Signaling Protects Against Doxorubicin-Induced Hepatic Injury in Rats

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Key Points

Structured PICO

Main Result

Limitations

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Implication

Abstract

Discussion

Cite This Study

Melatonergic Modulation of SIRT1-Nrf2 Signaling Protects Against Doxorubicin-Induced Hepatic Injury in Rats

Figures

Key Points

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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