Chronic diseases like diabetes, which affecting 463 million people worldwide, is a major public health concern (Chang and Nguyen, 2021). Diabetes is expected to become the seventh leading cause of death by 2030 (Saeedi et al., 2019), with a 25% increase in prevalence (Liu et al., 2018). Research suggests that 25–90% of amputations are caused by diabetic foot (Blume and Wu, 2018; Yang et al., 2022), and only 40–48% of patients survive five years after amputation (Li et al., 2020). Conservative diabetic wound care, comprising wound off-loading, debridement, and infection management (Everett and Mathioudakis, 2018), has mixed efficacy and adverse effects (Everett and Mathioudakis, 2018; Gottrup and Apelqvist, 2012). As a results, millions of people could benefit from diabetic wounds treatments that are both safe and effective.

Angiogenesis, according to what is known, is one of the primary processes involved in the healing of diabetic wounds. Inflammation, proliferation, and remodeling are the three stages of wound healing that normally occur over the course of few weeks (Chen et al., 2020). Unfortunately, diabetic wounds are notoriously difficult to heal because persistent inflammation impedes their progression to the proliferative phase, which in turn inhibits angiogenesis (Pang et al., 2021; Qian et al., 2022). In the proliferative phase, angiogenesis is a crucial factor reflecting the extent to which skin tissue regeneration and function restoration have occurred. Furthermore, encouraging angiogenesis can help with dermal regeneration and the development of healthy skin (Lin et al., 2020; Yuan et al., 2021). New blood vessels from the development of existing capillaries or post-capillary veins first appear on the wound bed 3–5 days after injury (Eming et al., 2007; Jeon et al., 2018) and promote the formation of granulation tissue (Bauer et al., 2005), then begin to construct a temporary matrix, which plays an important role in wound healing (Tonnesen et al., 2000). However, hyperglycemic environments of diabetic patients can impair vascular endothelial cell function, making it's difficult to generate mature blood vessels. This, in turn, limits extracellular matrix remodeling, granulation tissue formation, and wound healing in diabetic patients (Marino et al., 2014; Xian et al., 2019). For example, endothelial cells produce more reactive oxygen species (ROS) in response to hyperglycemia, and these ROS have been implicated as a cause of HG-induced impaired angiogenesis via DNA destruction and oxidative stress activation (Deng et al., 2021; Xia et al., 2019). Therefore, it's widely assumed that reducing oxidative stress will hasten and improve wound recovery. Various cytokines typically regulate cellular oxidative stress.

One of the most significant transcription factors in combating cellular oxidative stress is nuclear factor erythropoietin-2 associated factor 2 (Nrf2) (Ma, 2013), which is recognized as a critical regulator of redox homeostasis. Endothelial cells with lacking Nrf2 expression are unable to scavenge oxidative stress products, resulting in endothelial cell malfunction and apoptosis (Huang et al., 2022). Unfortunately, Nrf2 expression is frequently low in diabetic wound cells (Jayasuriya et al., 2020), preventing the site from creating the blood vessels needed for diabetic wound healing. As a result, boosting Nrf2 expression could potentially speed up the healing of diabetic wounds.

Gynura divaricata (L.) DC. (GD) is called “Bai Bei San Qi” in China and used in traditional Chinese medicine for its many pharmacological effects, including those of a hypoglycemic (Xu et al., 2020; Ye et al., 2022), insulin-sensitizing (Dong et al., 2019; Yin et al., 2018), and blood pressure-lowering agent (Hong et al., 2020). 3, 5-dicaffeoylquinic acid (3,5-diCQA) is also abundant in GD (Yin et al., 2018), and 3,5-diCQA has been shown to reduce oxidative stress (Bi et al., 2018; Liang and Kitts, 2018) and apoptosis in type 2 diabetic mice (Yin et al., 2018). Furthermore, GD has been shown to reduce oxidative stress levels in the livers of diabetic mice, demonstrating that GD can enhance antioxidant activity in vivo (Xu et al., 2015). Because of these, we set out to see if GD, via anti-oxidative stress and angiogenesis, could speed up the healing of diabetic wounds. This new role of GD in mediating diabetic wound healing is elaborated upon as additional research reveals that the beneficial effect of GD in diabetic wound healing is mediated by activation of the Nrf2 signaling pathway.