New research suggests that zinc not only supports immunity, but also reveals a complex molecular switch that may influence how the heart responds to inflammatory insults.

review: Zinc: metal shield against heart inflammation. Image credit: Cagkan Sayin / Shutterstock

In a recent review published in a magazine metalomicsresearchers synthesized a wide range of mechanistic and clinical literature studying the role of zinc (Zn) in cardiac regulation. inflammation. This review collated the literature on the biochemical, therapeutic, and immunological effects of zinc. Based primarily on mechanistic, observational, and preclinical evidence rather than definitive randomized clinical trials, we conclude that zinc deficiency is a potentially important but modifiable risk factor for cardiac inflammatory diseases (CID) such as myocarditis and pericarditis.

Zinc has been found to act primarily as an antioxidant cofactor and signaling molecule, with evidence suggesting that it may help regulate inflammatory cytokine signaling and oxidative stress pathways involved in cardiac tissue damage. While this review argues that zinc supplementation is a promising and accessible strategy to enhance future cardiovascular resilience, it highlights that much of the supporting evidence is preclinical or mechanistic in nature, and randomized controlled trials in patients with myocarditis or pericarditis are currently limited.

Biological importance of zinc and background of cardiac inflammation

Zinc (Zn) is an essential trace element that exists in trace levels in the human body. Despite its limited physiological amount (approximately 2 g), this metal is now known to be essential for immunomodulation, wound healing, and DNA synthesis.

In recent years, inflammatory heart diseases, particularly myocarditis and pericarditis, have received continued clinical and research attention. These symptoms are sometimes associated with sudden cardiac death in young people and athletes, and are frequently observed to be caused by viral infections (including SARS-CoV-2) or autoimmune responses.

Mechanistic studies suggest that these outcomes are caused by an autoimmune response, resulting in the release of significant concentrations of proinflammatory cytokines that damage the very tissues they are meant to protect.

Current interventions for inflammatory heart disease often focus on symptom management and broad immunosuppression. Although cardiac inflammation is multifactorial and cannot be attributed solely to zinc status, unfortunately these treatments rarely address the underlying nutritional or biochemical deficiencies that may contribute to dysregulated inflammatory responses.

Review scope and focus

This review synthesizes recent preclinical and clinical literature on the association between zinc deficiency and deleterious inflammatory heart diseases to determine whether zinc supplementation serves as an available and safe intervention against these potentially fatal cardiovascular diseases.

This review primarily focused on elucidating a relatively recently discovered biological mechanism, the “redox zinc switch.” In this biological mechanism, zinc is released from proteins during stress and then acts as a signal to regulate important inflammatory pathways (such as nuclear factor kappa B). [NF-κB]).

Additionally, this review summarized mechanistic, in vitro, and animal model evidence linking zinc homeostasis to ischemia (blood flow restriction) and reperfusion (blood flow restoration) injury and noted that direct assessment of cardiac zinc loss in humans remains technically challenging and that circulating plasma zinc concentrations may not reliably reflect intracellular cardiac zinc status.

Finally, this review evaluated the current and future therapeutic potential of zinc by focusing on zinc ionophores (molecules that facilitate zinc transport into cells) and specifically examining the effects of zinc on viral replication in studies conducted during the COVID-19 era.

Mechanistic pathways: anti-inflammatory and antioxidant roles

In this review, the protective function of Zn is attributed to three mechanistically distinct but physiologically interrelated biological functions.

First, Zn was found to act as a molecular “brake” on inflammation by inhibiting NF-κB, a protein complex previously shown to control DNA transcription and cell survival. This review found that under “normal” physiological conditions, NF-κB is inactive. However, infection triggers the release of inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α).

Specifically, Zn was shown to induce and promote A20 expression. A20 is a proteinaceous negative regulator that was found to effectively shut down the NF-κB signaling pathway. For example, in a study using the HL-60 cell line, zinc supplementation significantly enhanced A20 activity, thereby suppressing the inflammatory response.

Second, zinc exhibits strong antioxidant activity, making it an ideal therapeutic intervention for the heart, given its high susceptibility to oxidative stress due to reactive oxygen species (ROS). Zinc is known as an essential cofactor for the enzyme superoxide dismutase (Cu/Zn-SOD) and has been found to be an effective neutralizing species in the inactivation of toxic superoxide radicals.

Additionally, this review cites growing data showing that Zn inhibits NADPH oxidase, an enzyme involved in ROS generation, and promotes synthesis of glutathione, a powerful antioxidant.

Redox zinc switch and cell signaling

Finally, this review focuses on preclinical studies (animal models of cardiac ischemia) in which oxidative stress was found to release protein-bound Zn, a process now termed the “redox zinc switch.”

The released zinc was observed to act as a second messenger and protect cardiac tissue by activating protective signaling pathways such as PKC and MAPK. However, it was found that under conditions of zinc deficiency, this safety mechanism fails and these signaling proteins are degraded, leading to cell death and cardiac remodeling.

Conclusion and translation considerations

This review hypothesizes that maintaining optimal zinc levels (through diet or supplements) may provide preventive or adjunctive therapeutic effects in myocarditis and pericarditis. However, it has been highlighted that current blood-based zinc biomarkers have low sensitivity and often fail to detect marginal cell defects.

The authors suggest that future clinical strategies may need to utilize zinc ionophores, such as quercetin, to ensure that the mineral penetrates into the cardiac tissue where it is most needed. The paper concludes that clinical practice may need to reconsider zinc not just as a general immune support supplement, but as a targeted adjunct in strategies aimed at enhancing cardiovascular resilience, recognizing that both zinc deficiency and excessive supplementation can disrupt physiological homeostasis and require careful clinical consideration.