Myocardial infarction (MI), also known as heart attack, is a prevalent cardiovascular disease that poses a significant threat to human health. It is characterized by a high incidence and mortality rate, with millions of individuals worldwide suffering from ischemic heart disease and a substantial number of deaths attributed to MI each year [1], [2]. MI is characterized by progressive myocardial cell death, cardiac dysfunction, and structural changes in the heart following the blockage or narrowing of coronary arteries. This leads to myocardial ischemia, hypoxia, inflammation, and collagen deposition, resulting in impaired cardiac function and eventual heart failure [3], [4]. Cardiac fibrosis, a hallmark of post-MI pathology, plays a complex role in the healing and remodeling process [5], [6], [7]. While a controlled fibrotic response is necessary for cardiac repair, excessive or prolonged fibrosis can lead to scar formation and hinder optimal cardiac remodeling, contributing to heart failure [8]. Understanding the mechanisms underlying myocardial fibrosis after MI and effectively managing the inflammatory response and maladaptive fibrosis are crucial for developing new treatment strategies for MI and improving the management of heart failure patients.

In cardiovascular disorders, fibroblast-to-myofibroblast transition (FMT) is a crucial process driving cardiac fibrotic responses [9], [10]. Cardiac fibroblasts, which are abundant in the heart, play essential roles in the synthesis and degradation of extracellular matrix (ECM) proteins, as well as in chemical, mechanical, and electrical signaling within the heart [11], [12]. Under normal conditions, quiescent cardiac fibroblasts maintain the balance between ECM synthesis and degradation. However, in response to fibrogenic stimuli like Angiotensin II (Ang II) and transforming growth factor-β (TGF-β1), FMT occurs, leading to excessive ECM deposition and increased expression of alpha-smooth muscle actin (α-SMA) [10]. Following myocardial infarction (MI), myocardial fibrosis occurs, characterized by imbalanced ECM secretion and collagen deposition [13]. Reactive fibrosis in the early stages of MI is beneficial for limiting infarct expansion and promoting repair, but excessive reparative fibrosis in later stages can lead to ventricular remodeling and heart failure [14]. The process of FMT is closely associated with metabolic reprogramming, which influences fibrosis occurrence and progression [15]. Ang II and TGF-β1 can induce the expression of metabolic-related genes involved in glycolysis, contributing to fibrosis [16], [17], [18]. However, the specific metabolic changes in cardiac fibroblasts during MI-driven fibrosis and their impact on MI prognosis remain largely unknown. Further research is needed to elucidate these mechanisms and their potential implications.

Extensive foundational and preclinical research has focused on identifying key regulatory targets MI to explore novel treatment strategies. For instance, mutations in DNMT3A or TET2 are associated with increased inflammatory markers, leading to worse outcomes in ST-segment elevation myocardial infarction (STEMI) patients [19]. DYRK1A, through phosphorylation of WDR82 and KAT6A, reduces H3K4me3 and H3K27ac accumulation at cell cycle regulatory gene promoters in cardiomyocytes, influencing post-MI cardiac repair [20]. Furthermore, the Cystic Fibrosis Transmembrane Regulator (CFTR) is identified as a critical target in severe cognitive impairments following MI [21]. The role of the immune response in MI progression is also gaining attention. Cytokines, with their rapid and extensive immunomodulatory effects, are particularly noteworthy. A study on IL-6 inhibitor tocilizumab in STEMI and NSTEMI patients shows its impact on plaque instability and cardiac remodeling [22]. IL-34 has been found to maintain NF-κB pathway activation, increasing CCL2 expression and promoting macrophage recruitment and activation [23]. Preliminary research suggests that IL-22 plays a protective role in the heart by inhibiting myocardial cell apoptosis and reducing mitochondrial membrane potential and cytochrome C release during cardiac ischemia-reperfusion injury [24]. IL-22 is a cytokine that shares similarities with IL-10 and has been implicated in various cardiovascular diseases. While IL-22 has been shown to alleviate cardiac fibrosis in mouse models of myocardial infarction [18], the specific mechanisms underlying its role in cardiac fibrosis are not well understood. IL-22 can be secreted by different immune cells and binds to its receptor (IL-22R) on the cell surface, activating downstream signaling pathways. IL-22R is composed of IL-10R2 and IL-22RA1 chains, with IL-22RA1 mainly expressed in epithelial cells and fibroblasts [25]. Activation of IL-22R leads to the activation of JAK1-TYK2 and subsequent activation of the canonical STAT3 pathway, as well as non-canonical MAPK and PI3K/AKT pathways. While IL-22 has been shown to regulate metabolic reprogramming in other disease models [26], [27], [28], its impact on cardiac fibroblast metabolism in the context of myocardial infarction is not well-studied. Our study reveals the association between cardiac fibrosis, metabolic reprogramming of cardiac fibroblasts, and IL-22. IL-22 can alleviate cardiac fibrosis by modulating metabolic reprogramming, specifically downregulating aerobic glycolysis levels in cardiac fibroblasts through the activation of the JNK/PKM2 pathway. These findings provide insights into the metabolic regulation of cardiac fibrosis and suggest IL-22 as a potential therapeutic target for cardiac fibrosis in the context of myocardial infarction.