br The role of LOX plays

The role of 12/15-LOX plays in autophagy Autophagy is a process by which cellular material is delivered to lysosomal to degrade the damaged organelles and proteins to facilitate nutrient recycling (Towers and Thorburn, 2016). There has been characterized three types of autophagy-macroautophagy, microautophagy and chaperone mediated autophagy (CMA). The basic process of macroautophagy, usually referred to as autophagy involves the formation of double-membraned vesicles known as autophagosomes that engulfs cellular organelles and proteins, autophagosomes together with endosome to form the so-called amphisomes and the final fusion with lysosomes to form autophagy-lysosome (autophagolysosome) which degraded the contents to achieve the cell homeostasis and cell organelle regeneration (Rubinsztein et al., 2005). The pathological process of a variety of disease are involved in autophagy including cancer, neurological diseases, metabolic disorders, autoimmune disease and infectious (Levy et al., 2017). Over the past decades, numerous papers have found that autophagy was a double-edged sword. It's still unclear whether autophagy is a beneficial or detrimental in several disease including cancer, cardiovascular disease, ischemia and reperfusion (Choi, 2012; Gustafsson and Gottlieb, 2008; Sciarretta et al., 2011). Recently, an unanticipated relationship between lipoxygenases and autophagy has been revealed. Results have indicated that genetic ablation of 12/15-LOX could lead to enhanced autophagy by increasing the LC3-Ⅱ protein in the Palosuran and liver of mice. Similar results have been found in cultured HepG2 hepatoma cells and SH-SY5Y neuroblastoma cells by short-time pharmacological inhibition of LOXes. The enhanced macroautophagy was protective and this provide a vital clue to prevent accumulation of damaged mitochondrial and cellular components (Jang et al., 2014). A later study showed a novel role of 12/15-LOX in regulating autophagy. By isolating macrophages from the C57BL/6 wild type and 12/15-LOX−/− mice, authors examined the difference of membrane ultrastructure, LC3 expression and lipidation to determine the ability of oxidized phospholipids to act as substrates for LC3 lipidation in vitro. They firstly verified the functionally link between phospholipid oxidation with autophagy since they found that oxidized phospholipids generated by 12/15-LOX could act as substrates for key proteins required for effective autophagic and that cells deficient in this enzyme showed evidence of autophagic dysfunction (Morgan et al., 2015). A latest study indicated that pharmacological inhibition of 12/15-LOX was proved to be beneficial to cognitive impairment, brain amyloidosis and reversed tau pathology by stimulating autophagy through in aged triple transgenic (3xTg) mice. The results suggested that 12/15-LOX though modulating tau pathology was a modulator of autophagy in central nervous system (Di Meco et al., 2017). Results above indicated that 12/15-LOX showed a beneficial or detrimental role depended on the environmental conditions under which it was activated. In some cases, pharmacological inhibition of 12/15-LOX though facilitating autophagy serves as a viable therapeutic approach and an attractive class of candidate drugs for future medicinal development. (Fig. 2).
The role of 12/15-LOX plays in ferroptosis Ferroptosis is a recently identified new form of regulated cell death (RCD) which is different from apoptosis, necrosis and autophagy at genetic, morphological, and biological levels (Dixon et al., 2012a; Yang and Stockwell, 2016). It's characterized by increased cytoplasmic and lipid reactive oxygen species (ROS), condensed mitochondrial membrane density and smaller mitochondrial caused by accumulation of lipid peroxidation products and lethal ROS derived from ion metabolism (Mao et al., 2018). Ferroptosis can be induced by compounds including erastin, Ras-selective lethal small molecular 3 (RSL3), lanperisone, buthionine and so on and can be pharmacologically inhibited by lipid peroxidation inhibitors including ferrostatin, liproxstatin and zileuton and iron chelators including deferoxamine and desferrioxamine (Angeli et al., 2017; Latunde-Dada, 2017). Ferroptosis has been involved in many human diseases including cancer, neurodegenerative disorders, acute renal failure, reperfusion injure, drug-induced hepatotoxicity and T cell death (Cardoso et al., 2017; Guiney et al., 2017; Yu et al., 2017). Recently, LOX-mediated generation of lipid hydroperoxides has been supposed to be involved in ferroptosis. A study reported that the selective 12/15-LOX inhibitor and the pan-LOX inhibitor nordihydroguaiaretic acid protected acute lymphoblastic leukemia (ALL) cells against RLS3-induced ferroptosis which indicated that LOX contributed to the regulation of ferroptosis induced by RSL3-stimulated lipid peroxidation generation and cell death (Probst et al., 2017). Another study showed that 12/15-LOX inhibitors and siRNA-mediated silencing of ALOX15 protected cell death from erastin and RSL3-induced ferroptosis in oncogenic Ras-expressing cancer cells including HT1080 (human fibrosarcoma cell), Panc-1 (human pancreatic carcinoma cell) and Calu-1 (human non-small lung cancer). And the protective effect was linked to the LOX-catalyzed lipid hydroperoxide generation in cellular membranes since immunofluorescence analyses revealed that the ALOX15 protein consistently localized to cell membrane in the process of ferroptosis (Shintoku et al., 2017). The importance of esterified oxygenated PUFA was considered as a vital signal pathway contributing to ferroptosis. The enzymes involved in this process including ACSL4 (acyl-CoA synthetase long-chain family member 4), Elongase 5, LPCAT3 (lysophosphatidylcholine acyltransferase 3) and 12/15-LOX indicating that 12/15-LOX might serve as a key regulator to ferroptosis (Kagan et al., 2017). A recent study showed that 15-LOX isoforms, 15-LOX-1 and 15-LOX-2 could be regulated by phosphatidylethanolamine-binding protein 1 (PEBP1), a scaffold protein inhibitor of protein kinase cascades which was also known as RAF1 kinase inhibitory protein. Formation of PEBP1/15-LOX complexes could change the specificity of 15-LOX to catalyze the free PUFA to PUFA-PE which lead to the generation of HpETE-PEs. Insufficient or dysfunction of a selenoperoxidase, GPX4, failing to reduce the excessive HpETE-PEs led to ferroptosis. The signal pathway of PEBP1/15-LOX contributed to ferroptotic deaths in airway epithelial cells in asthma, kidney epithelial cells in renal faCELLilure, and cortical and hippocampal neurons in brain trauma. And this probably become a new target for drug discovery (Wenzel et al., 2017). Interestingly, studies have shown that reduced GSH leading to the activation of 12/15-LOX coincided with dysregulated Ca2+ ions mediated a form of programmed cell death which was similar to ferroptosis (Li et al., 1997; Maher et al., 2018). However, the relationship between 12/15-LOX and ferroptosis need to be further investigated (Fig. 3).