Nobiletin Ameliorates Doxorubicin-Induced Nephrotoxicity by Targeting Oxidative Stress, Inflammatory, and Apoptotic Pathways: Combined In Vivo and In Silico Insights

TL;DR

Nobiletin protects the kidneys from doxorubicin damage by reducing oxidative stress, inflammation, and cell death in rats.

Contribution

Nobiletin shows superior nephroprotective effects compared to silymarin and tangeretin through in vivo and in silico methods.

Findings

Nobiletin significantly reduced oxidative stress markers like MDA and improved serum albumin levels.

Nobiletin downregulated apoptotic and inflammatory genes such as CASP3, TNF-α, and PARP1.

Nobiletin showed better pharmacokinetic properties and oral absorption than silymarin.

Abstract

Doxorubicin (DOX), although effective as a chemotherapeutic
agent,
induces significant nephrotoxicity, limiting its clinical application.
This study investigated the nephroprotective potential of nobiletin
and tangeretin, in comparison with the reference compound silymarin,
against DOX-induced acute kidney injury (AKI) in rats. DOX administration
significantly increased the kidney-to-body weight ratio (p = 0.0053), elevated serum malondialdehyde (MDA) levels (11.49 ±
1.77 nmol/mL), and decreased serum albumin (ALB) levels (10.23 ±
1.84 mg/mL). These changes were accompanied by upregulation of oxidative
(NRF2 and HO-1), apoptotic (CASP3 and PARP1), and inflammatory (TNF-α, IL-1β, IL-6, and NF-κB) gene and protein
markers. Treatment with flavonoids significantly reversed these effects.
Improvements in ALB, MDA, and histopathological scores were observed
in all treatment groups without significant intertreatment differences.
Nobiletin notably reduced MDA to 8.12 ± 1.56 nmol/mL and restored
ALB to 15.89 ± 1.31 mg/mL (p < 0.01) while
also downregulating CASP3, TNF-α,
and PARP1 expressions. Histopathological analysis
showed that nobiletin provided substantial protection against tubular
necrosis, glomerular shrinkage, and interstitial inflammation, achieving
damage scores similar to the sham group. Furthermore, nobiletin and
silymarin both significantly reduced fibrotic area, whereas tangeretin
showed moderate effects. Molecular docking revealed that silymarin
had the most favorable binding affinities to targets such as CASP3,
TNF-α, and HO-1; however, its poor pharmacokinetic properties
(TPSA = 155.14 Å2) limited its systemic efficacy.
In contrast, nobiletin exhibited superior oral absorption (TPSA <
90 Å2) and dual CYP inhibition, contributing to better in vivo performance. The NRF2/HO-1 pathway was moderately
activated, with HO-1 protein levels elevated despite reduced mRNA,
suggesting post-transcriptional regulation. In conclusion, nobiletin
displayed a consistent multilevel protective profile, with notable
modulation of key apoptotic and inflammatory markers, while all compounds
provided comparable biochemical and histological benefits. These findings
support further development of nobiletin as a promising nephroprotective
agent in chemotherapeutic settings.

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