During mitophagy activation, Green1 is stabilized on depolarized or damaged mitochondria. its response item CO in apoptosis legislation continues to be characterized thoroughly, relatively fewer research have got explored the regulatory function of HO-1 in other styles of necrotic and inflammatory RCD (i.e., pyroptosis, necroptosis and ferroptosis). HO-1 Rhein-8-O-beta-D-glucopyranoside might provide anti-inflammatory security in pyroptosis or necroptosis. On the other hand, in ferroptosis, HO-1 may play a pro-death function via enhancing iron discharge. HO-1 continues to be implicated in co-regulation of autophagy also, a cellular homeostatic program for catabolic recycling of proteins and organelles. While autophagy is usually primarily associated with cell survival, its occurrence can coincide with RCD programs. This review will summarize the functions of HO-1 and its reaction products in co-regulating RCD and autophagy programs, with its implication for both protective and detrimental tissue responses, with emphasis on how these impact HO-1 as a candidate therapeutic target in disease. oxidase activity, and selectively induces HO-1 in a Rhein-8-O-beta-D-glucopyranoside species-specific manner, particularly in rodents [30,31]. HO-1 upregulation by these brokers occurs mainly by transcriptional upregulation of the gene (in rodents), and Rhein-8-O-beta-D-glucopyranoside results in de novo synthesis of the protein [32]. Considerable mechanistic studies have revealed that HO-1 gene regulation responds to positive regulation by nuclear factor erythroid 2-related factor-2 (Nrf2), a Capncollar/basic-leucine zipper family protein that can heteromerize with small Maf proteins [33]. Nrf2 is regarded as a grasp regulator of the antioxidant response and regulates a series of other genes involved in detoxification. The Kelch-like ECH-associated protein (Keap1) inhibits HO-1 expression by acting as a cytoplasmic anchor for Nrf2 under basal conditions [34,35]. Keap1 enables the targeting of Nrf2 by Cullin 3-based E3 ubiquitin ligase complex, which marks Nrf2 for proteasomal degradation [36,37]. When cells are exposed to inducing stimuli, Keap1 dissociates from Nrf2, which subsequently translocates to the nucleus, where it can activate gene expression, including the gene [33]. Transcription factor Bach-1 acts as a transcriptional repressor of HO-1 gene expression via competition with Nrf2 [31,38,39,40]. Heme can inhibit the DNA-binding activity of Bach-1 by direct binding, as well as promote the nuclear export of Bach-1 and inhibit the proteasomal degradation of Nrf2, hereby increasing HO-1 expression [38,39,41,42]. Both Nrf2 and Bach-1 target unique sites located in the promoter regions of genes. Comprehensive promoter analyses of the gene uncovered enhancer regions located at ?4 kb and ?10 kb relative to the transcriptional start site [43,44]. The dominant sequence element of the enhancers is the stress-responsive element (StRE), which is usually synonymous with the Maf response element (MARE) and antioxidant response element (ARE) [45,46]. A number of additional transcription factors have been implicated in HO-1 transcriptional regulation in a cell type-specific and inducer-specific fashion. These include AP-1 (Fos/Jun heterodimer), AP-2, warmth shock factor-1 (HSF-1), hypoxia-inducible factor-1 (HIF-1), early growth-1 protein (Egr-1), nuclear factor-kappa-B (NF-B), and cyclic AMP responsive element binding protein (CREB). The relative importance of these has been examined elsewhere [47,48]. In addition to regulation by transcription factor networks, emerging evidence suggests that HO-1 is usually post-transcriptionally regulated [49]. Several studies have implicated microRNAs (miRs) directly or indirectly in HO-1 regulation [50,51,52,53,54,55,56,57,58,59]. The miRs are small non-coding RNAs that can impact the outcome of gene expression by altering mRNA stability or translation. Previous studies have recognized miR candidates that can directly or indirectly influence HO-1 expression in a context-specific fashion. For example, miR-494 was found to promote HO-1 expression under oxidative stress conditions in neurons [50]. miR-378 overexpression was shown to downregulate HO-1 coincident with promotion of cell proliferation, whereas HO-1 expression reciprocally downregulated miR-378 [51]. Other miRs identified as influencing HO-1 regulation include inhibition by miR-24/mIR-24-3p [54], miR-200c [55], miR-155 [56], and miR-377/miR-217 [57]. Recent studies also implicate miRNA-dependent regulation of HO-1 in modulation of allergic inflammation (i.e., miR-205, miR-203, and miR-483-5p) [58], and iron-dependent neuroinflammation (miR-183-5p) [59]. Importantly, miRs can also indirectly regulate HO-1 via regulating the expression and/or stability of its upstream regulatory molecules, such as Nrf2 [55,60,61,62,63,64], or its cytoplasmic PDGFRA anchor molecule Keap1 [65,66]. For example, miR-101 promoted Nrf2 expression via inhibition of its ubiquitination [62], whereas miR-141-3p and miR200a were found to target Keap1, resulting in indirect activation of Nrf2 and HO-1 [65,66]. Several miRs (e.g., miR-155, mIR-196, let-7, miR-98-5p) can influence HO-1 expression through the downregulation of the transcriptional repressor Bach-1 [67,68,69,70]. HO-1 has also been implicated as an upstream functional influencer of miR networks, which in turn implicate downstream miR-dependent effects as possibly mediating the functional effects of HO-1 in various biological processes, including differentiation, angiogenesis, cell proliferation, inflammation and tumorigenesis [71,72]. For example, expression of HO-1 in myoblasts led to inhibition of specific (myo)miRs (e.g., miR-1, miR-133a/b, and miR-206) associated with inhibition of myoblast differentiation [73]. An effect of the.