Heme oxygenase 1 (HO-1) plays a key role in cell adaptation to stressors through the antioxidant, antiapoptotic, and anti-inflammatory properties of its metabolic products. For these reasons, in cancer cells, HO-1 can favor aggressiveness and resistance to therapies, leading to poor prognosis/outcome. Genetic polymorphisms of HO-1 promoter have been associated with an increased risk of cancer progression and a high degree of therapy failure. Moreover, evidence from cancer biopsies highlights the possible correlation between HO-1 expression, pathological features, and clinical outcome. Indeed, high levels of HO-1 in tumor specimens often correlate with reduced survival rates. Furthermore, HO-1 modulation has been proposed in order to improve the efficacy of antitumor therapies. However, contrasting evidence on the role of HO-1 in tumor biology has been reported. This review focuses on the role of HO-1 as a promising biomarker of cancer progression; understanding the correlation between HO-1 and clinical data might guide the therapeutic choice and improve the outcome of patients in terms of prognosis and life quality.

Induction of heme oxygenase 1 (HO-1) favors immune-escape in BRAF^V600 melanoma cells treated with Vemurafenib/PLX4032 under standard cell culture conditions. However, the oxygen tension under standard culture conditions (~18 kPa O₂) is significantly higher than the physiological oxygen levels encountered in vivo. In addition, cancer cells in vivo are often modified by hypoxia. In this study, MeOV-1 primary melanoma cells bearing the BRAF^V600E mutation, were adapted to either 5 kPa O₂ (physiological normoxia) or 1 kPa O₂ (hypoxia) and then exposed to 10 μM PLX4032. PLX4032 abolished ERK phosphorylation, reduced Bach1 expression and increased HO-1 levels independent of pericellular O₂ tension. Moreover, cell viability was significantly reduced further in cells exposed to PLX4032 plus Tin mesoporphyrin IX, a HO-1 inhibitor. Notably, our findings provide the first evidence that HO-1 inhibition in combination with PLX4032 under physiological oxygen tension and hypoxia restores and increases the expression of the NK ligands ULBP3 and B7H6 compared to cells exposed to PLX4032 alone. Interestingly, although silencing NRF2 prevented PLX4032 induction of HO-1, other NRF2 targeted genes were unaffected, highlighting a pivotal role of HO-1 in melanoma resistance and immune escape. The present findings may enhance translation and highlight the potential of the HO-1 inhibitors in the therapy of BRAF^V600 melanomas.

• A peptide vaccine that targets ANG2 reduced AVM number and size and normalized arterial and venous diameters in a mouse model of HHT. • The vaccine did not cause any abnormalities in cardiac, liver, or kidney functions and thus appeared safe.

Proprotein Convertase Subtilisin/Kexin type 9 PCSK9 inhibitors (PCSK9i) are a novel class of cholesterol-lowering agents that also offer protection against tissue ischemia by reducing apoptosis, pyroptosis, and myocardial infarct size. This study evaluated the effects of the PCSK9 inhibitor PEP 2-8 during hypothermic perfusion (HP) in a rat model of donation after circulatory death (DCD) kidney transplantation. DCD kidneys were perfused at 4 °C for six hours with either Perf-Gen solution alone (control) or Perf-Gen supplemented with PEP 2-8. Glucose and lactate dehydrogenase (LDH) levels were measured at baseline and after six hours (T6h). At T6h, kidneys were evaluated for ischemic injury, tubular cell proliferation, apoptosis, nitrotyrosine (N-Tyr) staining, tissue ATP and LDH levels, and gene expression of PCSK9 and NOX4. Metabolomic profiling was also performed. PEP 2-8 treatment significantly reduced PCSK9 expression, decreased tubular ischemic injury and necrosis, and lowered LDH release. Treated kidneys showed enhanced tubular cell proliferation, reduced apoptosis, and diminished oxidative stress, indicated by decreased N-Tyr staining and NOX4 expression. Energy metabolism was improved, with higher tissue ATP and glucose levels observed in the PEP 2-8 group. Metabolomic analysis further supported the antioxidant effects of PEP 2-8. This is the first study to demonstrate that PEP 2-8 administered during pre-transplant hypothermic perfusion provides renal protection by improving energy metabolism and reducing oxidative stress in the context of ischemic injury.