Antioxidants 2022, 11, 1551. https://doi.org/10.3390/antiox11081551 www.mdpi.com/journal/antioxidants Systematic Review Role of Nuclear Factor Erythroid 2 (Nrf2) in the Recovery of Long COVID-19 Using Natural Antioxidants: A Systematic Review Muchtaridi Muchtaridi 1, *, Siti Rafa Amirah 1 , Jacko Abiwaqash Harmonis 1 and Emmy Hainida Khairul Ikram 2 1 Department of Pharmaceutical Analysis and Medicinal Chemistry, Faculty of Pharmacy, Universitas Padjadjaran, Jl. Raya Bandung-Sumedang KM 21, Sumedang 45363, Indonesia 2 Faculty of Health Sciences, Universiti Teknologi MARA, Bandar Puncak Alam 42300, Malaysia * Correspondence: muchtaridi@unpad.ac.id Abstract: Coronavirus disease 2019 (COVID-19) is an infectious disease with approximately 517 million confirmed cases, with the average number of cases revealing that patients recover immedi- ately without hospitalization. However, several other cases found that patients still experience var- ious symptoms after 3–12 weeks, which is known as a long COVID syndrome. Severe acute respir- atory syndrome coronavirus 2 (SARS-CoV-2) infection can activate nuclear factor kappa beta (NF- κβ) and unbind the nuclear factor erythroid 2-related factor 2 (Nrf2) with Kelch-like ECH-associated protein 1 (Keap1), causing inhibition of Nrf2, which has an important role in antioxidant response and redox homeostasis. Disrupting the Keap1–Nrf2 pathway enhances Nrf2 activity, and has been identified as a vital approach for the prevention of oxidative stress and inflammation. Hence, natu- ral antioxidants from various sources have been identified as a promising strategy to prevent oxi- dative stress, which plays a role in reducing the long COVID-19 symptoms. Oxygen-rich natural antioxidant compounds provide an effective Nrf2 activation effect that interact with the conserved amino acid residues in the Keap1-binding pocket, such as Ser602, Ser363, Ser508, and Ser555. In this review, the benefits of various natural antioxidant compounds that can modulate the Nrf2 signaling pathway, which is critical in reducing and curing long COVID-19, are highlighted and discussed. Keywords: long COVID-19; Keap1; Nrf2; natural antioxidant 1. Introduction The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respir- atory syndrome coronavirus 2 (SARS-CoV-2) infection, has become a global health prob- lem worldwide [1]. Moreover, along with its development, SARS-CoV-2 mutated into var- ious variants, such as Alpha, Beta, Gamma, Delta, Omicron, Lambda, and Mu, drawing the world’s attention. Almost all these variants where data were available showed mild symptoms, such as anosmia, cough, flu, sore throat, and fatigue. Even the Omicron vari- ant causes milder symptoms and is generally asymptomatic, one of which is because there is a protein structure in the virus that does not undergo mutations so that it can induce the mechanism of action of the immune system of infected patients [2]. Various fields, including modern health, medicine, economy, and society, are af- fected by this pandemic. According to World Health Organization (WHO) data, as of 13 May 2022, there were 517,648,631 confirmed cases of COVID-19, including 6,261,708 deaths. With 60% of those infected recovering after 28 days without hospital treatment, most patients still experience various symptoms after 3–12 weeks, known as the long COVID syndrome [1,3]. Regardless of the virus variant, one of the causes of long COVID is due to the im- paired expression of antioxidant enzymes and cytoprotective proteins that are regulated Citation: Muchtaridi, M.; Amirah, S.R.; Harmonis, J.A.; Ikram, E.H.K. Role of Nuclear Factor Erythroid 2 (Nrf2) in the Recovery of Long COVID-19 Using Natural Antioxidants. Antioxidants 2022, 11, 1551. https://doi.org/10.3390/ antiox11081551 Academic Editor: Dimitrios Kouretas Received: 12 July 2022 Accepted: 7 August 2022 Published: 10 August 2022 Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional claims in published maps and institu- tional affiliations. Copyright: © 2022 by the authors. Li- censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con- ditions of the Creative Commons At- tribution (CC BY) license (https://cre- ativecommons.org/licenses/by/4.0/).