Abstract: Cell Stress and Chaperones (2020) 25:707–710 https://doi.org/10.1007/s12192-020-01126-9 PERSPECTIVE AND REFLECTION ARTICLE COVID-19 and heme oxygenase: novel insight into the disease and potential therapies Philip L. Hooper 1 Received: 14 May 2020 / Revised: 22 May 2020 / Accepted: 25 May 2020 / Published online: 4 June 2020 # Cell Stress Society International 2020 Abstract The COVID-19 pandemic needs therapies that are presently available and safe. We propose that subjects with metabolic syndrome, old age, and male gender have the greatest morbidity and mortality and have low stress proteins, in particular, low intracellular heme oxygenase (HO-1), making them particularly vulnerable to the disease. Additionally, COVID-19’s heme reduction may contribute to even lower HO-1. Low-grade inflammation associated with these risk factors contributes to triggering a cytokine storm that spreads to multi-organ failure and near death. The high mortality of those treated with ventilator assistance may partially be explained by ventilator-induced inflammation. The cytoprotective and anti-inflammatory properties of HO-1 can limit the infection’s damage. A paradox of COVID-19 hospital admissions data suggests that fewer cigarettesmokers are admitted compared with non-smokers in the general population. This unexpected observation may result from smoke induction of HO-1. Therapies with anti-viral properties that raise HO-1 include certain anesthetics (sevoflurane or isoflurane), hemin, estrogen, statins, curcumin, resveratrol, and melatonin. Controlled trials of these HO-1 inducers should be done in order to prevent or treat COVID-19 disease. Keywords Heme oxygenase . COVID-19 . Therapy . Heat shock proteins . Ventilator . Inflammation . Cytokine storm . Smoking . Estrogen . Anesthesia . Elderly The pandemic of COVID-19 virus caught the world unprepared. The reported deaths by the virus in the USA are now almost two times the number of US servicemen that died in the Viet Nam conflict—over 90,000 dead. This tragedy occurred in just three months. Effective treatment is not immediately evident. We propose stress proteins and in particular heme oxygenase 1 (HO-1, Hsp32) may play a role in the virus’ pathological impact and as a therapeutic modality. Conditions associated with a higher morbidity and mortality from COVID-19 infection are characteristics of the metabolic syndrome (insulin resistance, diabetes, obesity, hypertension, cardiovascular disease), old age, male gender, and mechanical ventilator support. Pertinently, these groups generally have lower intracellular stress protein levels including low HO-1. Low intracellular stress proteins make these * Philip L. Hooper phoopermd@gmail.com 1 Division of Endocrinology and Metabolism, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA populations vulnerable to stress from whatever type of assault, whether infection, trauma, or poison (De Maio and Hightower 2020) (Hooper and Hooper 2005). Individuals with metabolic syndrome and insulin resistance have low-grade inflammation that can set a milieu for COVID-19 infection to trigger a cytokine storm, a common near-terminal event with multiorgan damage seen in COVID infection. (Mehta et al. 2020) Indeed, knocking out HO-1 genes in animal models increases lung damage caused by sepsis. (Chen et al. 2018) Conversely, raising HO-1 and other stress reduces inflammation and improves insulin resistance and in animal models..