## 3 Discussion  
Keap1, the primary intracellular regulator of Nrf2, is composed of five key domains (Figure 6): three broad complex-tramtrack-bric a brac (BTB) domains, one intervening region (IVR) domain, and two glycine repeat (DGR) domains, each playing a vital role in controlling Nrf2 activity. The BTB domains, located at the N-terminal part of Keep1, are crucial for Keep1 dimerization and interaction with other transcription factors, thereby stabilizing Keep1's structure. The IVR domain, positioned between the BTB and DGR domains, contains a nuclear export signal sequence essential for retaining Keep1 in the cytoplasm and interacting with E3 ligase complexes like Cul3-Roc1 [48]. On the other hand, the DGR domains, found at the C-terminal end of Keep1, are responsible for binding to the DLG and ETGE motifs on Nrf2, facilitating its ubiquitination and degradation under normal conditions. These domains are also essential for detecting and responding to oxidative stress by modulating Nrf2 binding, allowing Nrf2 to translocate into the nucleus and activate antioxidant genes. Together, these domains regulate the balance between stabilizing Nrf2 and responding to stress signals, thereby maintaining cellular health by controlling genes involved in detoxification and protection against oxidative damage [49]. Recent research underscores that the Keep1-Nrf2-ARE pathway plays a crucial role in regulating the body's antioxidant defense system and detoxification mechanisms, making it a compelling therapeutic target for oxidative stress-related disorders. Flavonoids, particularly those derived from citrus, such as hesperidin, naringin, and nobiletin, have shown significant potential as dietary antioxidants capable of modulating the Keep1\(-\)Nrf2 interaction [50]. These compounds activate Nrf2 by disrupting its binding with Keep1 through mechanisms such as phosphorylation, autophagic degradation, and epigenetic modifications. Experimental and computational studies reveal that citrus-derived flavonoids exhibit strong binding affinity with Keep1 through stable hydrogen bonding and hydrophobic interactions, classifying them into strong and weak agonists based on their antioxidant response element (ARE) activation capabilities [51]. In the context of respiratory viral infections, including SARS-CoV-2, Nrf2 activators demonstrate protective effects by reducing ACE2 receptor expression, mitigating oxidative stress, and enhancing antiviral responses, thus lowering disease severity. However, despite promising in silico and in vitro findings, challenges remain in translating these results into clinical applications. Issues such as the poor bioavailability of flavonoids and the lack of robust human studies highlight the need for advanced drug delivery systems and comprehensive clinical trials to optimize their therapeutic efficacy for oxidative stress and inflammation-related diseases, including COVID-19 and its complications [52]. Interestingly, apigenin, a flavonoid identified in olive oil, holds promising therapeutic and prophylactic potential for managing post-COVID-19 syndrome due to its multifaceted bioactivities. As demonstrated by docking studies and in vitro experiments, apigenin exhibits moderate antiviral properties against SARS-CoV-2 through a strong binding affinity to viral RNA-dependent RNA polymerase (RdRP), suggesting its utility in disrupting viral replication [53]. Furthermore, apigenin's potent anti-inflammatory and antioxidant properties, including modulation of cytokine release and inhibition of enzymes like phospholipase A2 (PLA2-IIA), address key drivers of chronic inflammation and oxidative damage observed in post-COVID-19 conditions. These features, combined with its adherence to [PERSON]'s rule and favorable ADMET profiles, underscore apigenin's potential as a critical component in supportive care strategies aimed at mitigating long-term complications, including pulmonary fibrosis and systemic inflammation, in post-COVID-19 patients [54].