ST-segment elevation myocardial infarction (STEMI) is characterized by complete occlusion of a major coronary artery and represents a severe clinical presentation of ischemic heart disease. Global data indicate that ischemic heart disease affected an estimated 254.28 million people and caused 8.99 million deaths worldwide in 2021(1). Rapid restoration of coronary blood flow is key in salvaging ischemic myocardium and improving patient outcomes. Primary percutaneous coronary intervention (PCI) has become the most established method for treating STEMI and can effectively restore flow in the infarct-related artery. However, the reperfusion process itself may paradoxically induce further myocardial injury, known as ischemia-reperfusion injury (IRI) (2). IRI markedly increases the final infarct size and contributes to adverse left ventricular remodeling, ultimately affecting long-term cardiac function and increasing the risk of heart failure. The underlying mechanisms of IRI are complex and multifactorial, involving oxidative stress, inflammation, calcium overload and mitochondrial dysfunction. Specifically, abrupt reperfusion induces a burst of reactive oxygen species that damages cell lipids, proteins and DNA; inflammatory cell activation and cytokine release further exacerbate endothelial and myocardial injury; calcium overload promotes cardiomyocyte hypercontracture and activation of calcium-dependent enzymes and mitochondrial dysfunction impairs ATP production and triggers cell death (2). Therefore, IRI has become a challenging clinical issue with limited treatment options currently available.

Iron metabolism serves a key role in maintaining normal myocardial function. Iron is an important component of hemoglobin and myoglobin, participating in the transport and storage of oxygen and is also important for the energy metabolism of cardiomyocytes (3). Dysregulation of iron metabolism, particularly iron overload, has been associated with the occurrence and development of a number of cardiovascular diseases, including atherosclerosis, heart failure and myocardial ischemia-reperfusion injury (3). Excess iron can catalyze the production of reactive oxygen species (ROS) through the Fenton reaction, resulting in oxidative stress and lipid peroxidation, which damage cell membranes and organelles (4). Furthermore, iron overload may activate inflammatory pathways, including NF-κB-mediated signaling and downstream cytokine release, such as TNF-α and IL-6, thereby exacerbating inflammatory responses and further injuring cardiomyocytes (5). Ferritin, hepcidin, heme and heme oxygenase-1 (HO-1) are key regulatory factors of iron metabolism whose roles in cardiovascular diseases have garnered increasing attention (3,5). Ferritin is a notable intracellular iron-storage protein, and serum ferritin is commonly used as a surrogate marker of body iron stores, although it may also be influenced by inflammation and tissue injury (3,5). Hepcidin is the key hormone in regulating iron homeostasis, predominantly produced by the liver and it inhibits iron absorption and release. Heme is the prosthetic group of hemoglobin and myoglobin and exhibits pro-oxidative and pro-inflammatory effects, whereas HO-1 is a protective enzyme with antioxidant and anti-inflammatory properties that can degrade heme. Given that iron overload, oxidative stress and inflammation are all central to IRI pathology, it was hypothesized that disordered iron metabolism may serve an important role in IRI following direct PCI in patients with STEMI (5).

The present study aimed to investigate the dynamic changes in iron metabolism indices (including ferritin, hepcidin, heme and HO-1) in patients with STEMI following direct PCI and analyze the association between these indices and IRI. The present study aimed to expand the current understanding of the role of iron metabolism in the development of IRI and discuss whether these iron metabolism indices could serve as potential biomarkers and therapeutic targets for IRI.

The present study aimed to investigate the changes in iron metabolism indices (ferritin, hepcidin, heme and HO-1) in patients with STEMI after primary PCI, grouping them by the presence or absence of IRI. The findings revealed that post-PCI ferritin was significantly increased compared with pre-PCI levels among patients with STEMI. The ferritin elevation in patients with IRI was significantly greater compared with that in the non-IRI group. Likewise, the change in hepcidin in patients with IRI was also higher compared with the non-IRI group. Although no statistically significant difference was observed between groups, both heme and HO-1 levels tended to increase after primary PCI and, compared with patients without IRI.

IRI is a complex and multifactorial pathophysiological process in patients with STEMI undergoing primary PCI. The reported incidence of IRI ranges from 11-48% (2). In the present study, the incidence of IRI was 44.1%. The occurrence of IRI is associated with multiple factors, including ischemic duration, ischemic severity, reperfusion strategy and the baseline disease status of the patient. In the present study, the IRI group exhibited a significantly higher NT-proBNP level upon admission compared with the non-IRI group (P=0.026), suggesting a heavier cardiac burden, consistent with previous findings that elevated NT-proBNP is associated with the extent of myocardial damage and the severity of IRI (10). Furthermore, although it did not reach statistical significance (P=0.053), the IRI group had a higher granulocyte count, suggesting inflammation may serve a role in the development of IRI (11).

The present findings demonstrated that, despite the lack of statistically significant baseline differences, the IRI group of patients with STEMI experiencing IRI after PCI displayed a significantly greater ferritin elevation (P=0.016) compared with the non-IRI group. These findings indicate an association between dysregulated iron metabolism and IRI; however, given the observational design, causality cannot be inferred and residual confounding cannot be excluded. Ferritin is the major iron-storage protein, and its elevated level generally reflects increased iron content in the body or disordered iron metabolism (12). During IRI, myocardial cell damage and necrosis lead to the release of intracellular iron to the circulation, raising ferritin levels (13). Furthermore, ROS produced during IRI can promote the release and degradation of ferritin, further exacerbating iron overload (14). Free iron can catalyze ROS production through the Fenton reaction, resulting in lipid peroxidation, protein oxidation and DNA damage, aggravating myocardial damage and apoptosis (15). Simultaneously, iron overload may activate inflammatory cascades and promote the release of inflammatory cytokines, such as TNF-α, IL-1β and IL-6, further worsening the inflammatory injury of IRI (16). Hepcidin is a key hormone regulating iron metabolism, functioning mainly by inhibiting iron absorption and release. The present study showed that the magnitude of change in hepcidin in patients with IRI was also significantly higher compared with that in patients without IRI (P=0.016), potentially being associated with inflammatory response, as inflammation can elevate the synthesis and release of hepcidin, promoting intracellular iron retention and exacerbating iron overload and oxidative stress injury (17).

The present study demonstrated that heme levels exhibited an upward trend post-PCI in patients with STEMI both in the IRI and non-IRI groups. However, the difference between the groups was not statistically significant. Notably, although there were no statistically significant differences in heme levels between the two groups before PCI (P=0.544) and after PCI (P=0.975), the heme levels in the IRI group were higher compared with those in the non-IRI group. This trend suggests that heme may serve a role in the pathophysiological mechanisms of IRI. One possible explanation is that patients in the IRI group had higher baseline heme levels, reflecting an inherent susceptibility to oxidative stress and inflammation, which are primary drivers of IRI. This may predispose these patients to greater myocardial injury upon reperfusion. Heme is a component of hemoglobin and myoglobin, serving a key role in oxygen transport and storage. During IRI, myocardial cell damage and hemolysis can lead to the release of heme into the bloodstream (18). Free heme possesses pro-oxidant and pro-inflammatory properties, exacerbating tissue damage caused by IRI (19). It can catalyze the production of ROS through Fenton reactions, leading to lipid peroxidation, protein oxidation and DNA damage (20). Additionally, heme can activate inflammatory cascades, including TLR4-mediated signaling and downstream NF-κB activation, thereby promoting the release of inflammatory cytokines such as TNF-α, IL-1β and IL-6, thereby further intensifying the inflammatory response and tissue injury (16,19). Furthermore, it should be noted that the magnitude of heme level changes in the IRI group was smaller compared with the non-IRI group (a median increase of 0.4 µmol/l in the IRI group vs. a median increase of 5.1 µmol/l in the non-IRI group; P=0.307), although this difference did not reach statistical significance. This may suggest an impaired capacity for clearance or metabolism of free heme in patients with IRI. Reduced clearance efficiency could lead to sustained elevated heme levels in these patients, thereby exacerbating oxidative damage. However, the role of heme is not entirely detrimental. Previous studies have indicated that lower concentrations of heme may induce the expression of HO-1, exerting antioxidant and anti-inflammatory protective effects (21,22). Therefore, the role of heme in IRI may be dualistic, with its ultimate effect depending on its concentration, duration of action and the physiological state of the organism.

HO-1 is a protective enzyme with antioxidant and anti-inflammatory properties that catalyzes the degradation of heme into biliverdin, carbon monoxide and free iron (21). In the present study, HO-1 levels exhibited an upward trend post-PCI in both the IRI and non-IRI groups of patients with STEMI, although the difference between the groups was not statistically significant. Upregulation of HO-1 may represent an endogenous protective mechanism of the body attempting to counteract the oxidative stress and inflammatory responses induced by IRI (22). The protective effects of HO-1 are primarily mediated through its degradation products biliverdin, carbon monoxide and bilirubin. Biliverdin and bilirubin are effective antioxidants that can scavenge ROS and inhibit lipid peroxidation (23). Carbon monoxide exerts anti-inflammatory, anti-apoptotic and vasodilatory effects (24). However, the modest increase in HO-1 observed in the present study suggests that this protective mechanism may be insufficient to fully offset the damage caused by IRI. This insufficiency could be due to inadequate induction of HO-1 during the IRI process or the inhibition of HO-1 activity.

The results of the present study indicate that there were differences in the magnitude of changes in heme and HO-1 levels post-PCI between the IRI and non-IRI groups of patients with STEMI, although these differences did not reach statistical significance. In the IRI group, the median change in heme was an increase of 0.4 µmol/l, whereas in the non-IRI group it was an increase of 5.1 µmol/l (P>0.05). For HO-1, the median change in the IRI group was an increase of 0.1 ng/ml, compared with an increase of 1.2 ng/ml in the non-IRI group (P=0.230). These findings suggest that, although both groups exhibited trends of increased heme and upregulated HO-1 post-PCI, the increases in heme and HO-1 were smaller in the IRI group. However, because these between-group differences were not significant, any mechanistic interpretation should be made with caution.

Based on the observed associations between changes in iron metabolism parameters and IRI, therapeutic strategies targeting iron handling and downstream oxidative/inflammatory pathways (such as iron chelation, antioxidant therapy or HO-1 modulation) merit further investigation. Notably, the present observational study did not establish causality or therapeutic efficacy; therefore, these strategies should be evaluated in adequately powered randomized clinical trials and mechanistic studies before clinical application. Iron chelators can mitigate oxidative stress damage by binding free iron ions, thereby inhibiting Fenton reactions and reducing the generation of ROS (25). In addition, iron chelators can decrease iron-mediated inflammatory responses, further protecting myocardial cells. Another potential therapeutic target is antioxidants, which can directly scavenge ROS, inhibit lipid peroxidation and protein oxidation, thereby alleviating oxidative stress damage (26). Furthermore, a number of antioxidants can enhance endogenous protective mechanisms by upregulating HO-1 expression. The direct use of HO-1 inducers or HO-1 gene therapy may also serve as potential therapeutic strategies (18); however, further research is needed to verify their safety and efficacy.

The present study exhibits a number of limitations that should be considered when interpreting the results. First, the sample size was relatively small, which may have resulted in insufficient statistical power, especially in subgroup analyses such as comparisons between the IRI and non-IRI groups. Second, the single-center design may have limited the generalizability of the findings. Third, as an observational study, multivariable adjustment was not performed; therefore, residual confounding cannot be excluded, and the observed associations should be interpreted as simple associations rather than evidence of causality. Given the sample size and event number, more complex multivariable models may increase the risk of overfitting. Future larger multicenter prospective studies with multivariable analyses and mechanistic investigations are warranted.

In conclusion, following primary PCI in patients with STEMI, the levels of ferritin and hepcidin increased, with more pronounced post-PCI rises in patients with IRI. Heme and HO-1 showed upward trends without statistically significant inter-group differences. Overall, these findings support an association between altered iron/heme metabolism and the occurrence of IRI, suggesting that serial ferritin and hepcidin assessment may be explored as candidate biomarkers for early risk stratification, while iron-related pathways merit further investigation as potential therapeutic targets. However, given the single-center observational design, the limited sample size and the lack of multivariable adjustment, the results of the present study should be interpreted cautiously and require further determination in larger multicenter cohorts with multivariable analyses.