
-   Srxn1 is an endogenous antioxidant that has been shown to prevent exogenous compound-induced oxidative stress [PMID: 31079497]. Downregulation of Srxn1, important signaling molecules in the NRF2 signaling pathway, can also make cells more susceptible to ferroptosis [PMID: 30692038].
-   Srxn1 is crucial for defending neurons and astrocytes against oxidative stress through various mechanisms including Prdxs, JNK/c-Jun, EGFR-Nrf2 and the Notch signaling pathway [PMID: 31079497, PMID: 32949970, PMID: 25582778, PMID: 23553940, PMID: 25407820, PMID: 21177433], and it plays a protective role against apoptosis in conditions like oxygen-glucose deprivation/reperfusion [PMID: 33421493, PMID: 25955519, PMID: 25620665]. Its association with reduced cognitive decline presents it as a promising blood biomarker for cognitive impairments [PMID: 35242306], and its ability to modulate oxidative stress positions Srxn1 as a potential therapeutic target for neurodegenerative disorders and cerebral ischemia reperfusion injury [PMID: 27821734, PMID: 28552673]. Srxn1's role in neuroprotection is supported by its mediation through the Nrf2/Srxn1-ERK1/2 MAPK pathway, offering insights into treatments for conditions like multiple sclerosis [PMID: 26090715]. The activation of the Nrf2/Srxn1 pathway by bilirubin oxidation end products in cortical neurons suggests a protective role against oxidative stress in delayed ischemic neurological deficit following subarachnoid hemorrhage [PMID: 34373769].
-   Srx-1 plays a critical role in cardioprotection by suppressing PI3K/AKT-mediated mitochondrial apoptosis during ischaemia/reperfusion injury [PMID: 26992405] and enhancing the survival of cardiac progenitor cells against oxidative stress through ERK/NRF2 signaling pathway, thus facilitating the repair of the infarcted myocardium [PMID: 29772252, PMID: 29675777]. Moreover, high potassium concentration in Del Nido cardioplegic solution induces Nrf2 and Srxn1 expression, protecting cardiomyocytes from oxidative damage [PMID: 37842750]. The Nrf2/Srxn1 pathway is also implicated in atherosclerosis plaque formation, suggesting its complex role in cardiovascular health and disease [PMID: 37842750].
-   Srxn1 overexpression defends against diabetic complications by enhancing protective signaling pathways. In retinal ganglion cells, it mitigates high glucose-induced injury through Nrf2 signaling modulation by the Akt/GSK-3 beta axis, offering potential defense against diabetic retinopathy [PMID: 34653733]. Srxn1 also acts as a crucial protective mechanism in diabetic cardiomyopathy by modulating ROS signaling and reducing hyperoxidized peroxiredoxins [PMID: 28202395]. Additionally, it alleviates high glucose-induced podocyte injury by promoting Nrf2/ARE signaling through GSK-3 beta inactivation, suggesting a protective role in diabetic nephropathy [PMID: 31284950].
-   Srxn1 expression increased in the pancreatic tissue of mild acute pancreatitis (AP) but decreased in severe AP mouse models. Overexpression of Srxn1 attenuated AP symptoms by reducing ROS levels, acinar cell apoptosis, and inflammatory responses through the modulation of the ROS/ER stress/Cathepsin B pathway [PMID: 34140464].
-   The Aryl hydrocarbon receptor (AhR) is instrumental in bolstering antioxidant defenses against oxidative stress from cigarette smoke by upregulating Srxn1 expression via mechanisms such as miR-96, thereby offering protection against the development or progression of COPD [PMID: 28079158, PMID: 26408075]. Elevated Srxn1 levels in the airway epithelial cells of COPD smokers, as opposed to non-smokers, underscore its pivotal role in counteracting the detrimental effects of cigarette smoke on respiratory health [PMID: 35433978].
-   Srxn1's overexpression promotes tumorigenesis by enhancing MAPK, Wnt/beta-catenin, ROS/p65/BTG2 signaling and interacting with proteins such as S100A4, leading to poor patient survival [PMID: 24503444, PMID: 28448437, PMID: 32746503, PMID: 21487000, PMID: 22934964, PMID: 22016591, PMID: 21943684, PMID: 24189098]. Srxn1, by forming a complex with TXNDC5, supports cancer cell survival under ER stress [PMID: 31000628]. Srxn1 can also promote invasion and metastasis via upregulation of T-cadherin [PMID: 28351308], EGFR signaling [PMID: 26290602]. Srxn1 knock-down or knock-out has shown potential in inhibiting tumor growth, underlining its role in tumor pathogenesis [PMID: 35071014, PMID: 21487000, PMID: 24503444, PMID: 23393226, PMID: 26721593, PMID: 29906488].
-   Studies on Srxn1 null mice and cells indicate a general trend of reduced tumor incidence [PMID: 23393226], colony formation [PMID: 19057013, PMID: 21487000], and invasiveness [PMID: 22934964], with no significant impact on cell proliferation in skin tumors [PMID: 24503444]. Depletion of Srxn1 led to decreased tumor multiplicity in colon carcinomas [PMID: 23393226, PMID: 24503444] and reduced tumor volume in skin tumors [PMID: 24503444], alongside an increase in intra-tumoral apoptotic cells [PMID: 22086924, PMID: 24503444]. Sulfiredoxin (Srxn1) inhibition or depletion triggers the accumulation of sulfinylated peroxiredoxins and ROS, leading to oxidative stress, mitochondrial damage, and apoptotic death in cancer cells. This suggests that targeting Srx could be a viable therapeutic approach for cancer treatment by exploiting redox-mediated cell death mechanisms [PMID: 27825965, PMID: 26721593].

## Summary

Srxn1 encodes the enzyme sulfiredoxin 1 which specifically targets hyperoxidized 2-cys peroxiredoxins including PRDX1, PRDX2, PRDX3, and PRDX4, reducing the sulfinic form (-SO2H) of the peroxiredoxin active site cysteine back to the sulfenic form (-SOH). This regeneration is vital as peroxiredoxins are responsible for breaking down hydrogen peroxide, a reactive oxygen species, thereby mitigating oxidative stress within hepatocytes [CS: 9]. In the context of pervasive exogenous and endogenous oxidative insults that the liver must process, such as xenobiotics and metabolic byproducts, maintaining functional peroxiredoxins is essential for cell survival and detoxification efficiency [CS: 8].

In diseases like hepatocellular carcinoma (HCC) and during certain toxic exposures like glutathione depletion, the liver experiences heightened levels of oxidative stress, prompting an increase in Srxn1 gene expression [CS: 7]. The elevated Srxn1 gene expression allows for greater production of sulfiredoxin-1, enhancing the cellular capacity to repair oxidatively modified peroxiredoxins and maintain the redox balance within hepatocytes [CS: 8]. This adaptive response to increased oxidative stress aims to preserve liver function and survivability under adverse conditions [CS: 8]. Additionally, SRXN1 upregulation triggers downstream antioxidant defense pathways regulated by the transcription factor Nrf2 [CS: 9]. The activation of the Nrf2 pathway boosts the production of additional antioxidant enzymes like glutathione-S transferase and hemeoxygenase-1, further strengthening the cell's protective mechanisms against oxidative stress [CS: 9].
