# Protective effects of naringenin and naringin in organ ischemia/reperfusion injuries: a comprehensive narrative review

## TL;DR

This review explores how naringenin and naringin, natural flavonoids, may protect organs from damage caused by ischemia and reperfusion.

## Contribution

The paper comprehensively reviews the protective mechanisms and signaling pathways of naringenin and naringin against organ ischemia/reperfusion injuries.

## Key findings

- Naringenin and naringin protect multiple organs from IRI through antioxidant, anti-inflammatory, and anti-apoptotic effects.
- They modulate key signaling pathways like NF-κB, Nrf2, and PI3K/AKT to reduce IRI damage.
- Challenges remain regarding bioavailability and clinical safety of naringenin and naringin.

## Abstract

Ischemia/reperfusion injury (IRI) refers to a condition in which ischemia is followed by reperfusion, leading to an exacerbation of the initial tissue damage. Currently, there are no specific therapeutic methods for IRI. Phytochemicals from natural products have the potential to develop noble drugs for IRI. Naringenin (NGE) and naringin (NG) are natural dietary flavonoids derived from ethnobotanical plants in Southeast and South Asia. NGE and NG have a wide range of pharmacological properties, including antioxidant, anti-apoptotic, and anti-inflammatory effects. As research on NGE and NG deepens, it has been found that they protect against IRI. We first summarize plant species containing NGE and NG from Southeast and South Asia in this article. Then, we highlight recent advances in NGE and NG for treating IRI in the myocardium, brain, intestines, kidneys, retinal, liver, spinal cord, skeletal muscles, and testicles. We find that NGE and NG possess antioxidant, anti-inflammatory, anti-apoptotic, anti-endoplasmic reticulum stress, anti-ferroptosis, anti-pyroptosis, and autophagy regulatory properties that protect organs from IRI. In addition, NGE and NG alleviate organ IRI through certain signaling pathways, including nuclear factor-κB, nuclear factor erythroid 2-related factor 2, phosphatidylinositol 3-kinase/AKT, cyclic guanosine monophosphate–adenosine monophosphate synthase–stimulator of interferon genes, sirtuin (SIRT) 1/SIRT 3, and hypoxia-inducible factor-1α. Furthermore, we investigate the interactions between these signaling pathways and inflammation, oxidative stress, and programmed cell death. Nevertheless, NGE and NG still face challenges related to pharmacokinetic interactions, bioavailability, and clinical safety assessments. Further studies will be needed to verify their safety and efficacy in clinical settings.