The thioredoxin domain containing protein-5 (TXNDC5), also known as ERP46 (1), HCC-2, STRF8, PDIA15, UNQ364, endo PDI, is a member of the PDI family that is located on chromosome 6p24.3. Full-length cDNA analysis indicated that TXNDC5 is a 48 kDa protein measuring 845.2 kbp. It can encode five splice variants, of which TXNDC5-001 and TXNDC5-003 can be translated into proteins (2). TXNDC5 is widely distributed across tissues, mainly in the brain, spleen, lung, liver, kidney, pancreas, testis and others. TXNDC5 is highly expressed in endothelial cells and in the endothelium of tumors and atherosclerotic plaques, and TXNDC5 is upregulated in hypoxic conditions (1, 3–5). It is also upregulated in autoimmune diseases such as rheumatoid arthritis and highly expressed in various organ fibrosis diseases. Previous studies have shown that TXNDC5, like other PDI family members, regulates disulfide bond formation and rearrangement through the CxxC motif and assists in the proper folding of oxidized residue disulfide bonds (5–7). TXNDC5 functions as a stress survival factor and is required for endothelial cell survival under hypoxic conditions (3). TXNDC5 can mediate tumor necrosis factor-α (TNF-α) induced angiogenesis (8). TXNDC5 can bind to lipocalin receptor 1 as a cellular adapter and participate in cellular metabolism and inflammatory responses by activating downstream inflammatory factors (9). TXNDC5 can bind to alpha -mannosidase–like protein 3 (EDEM3) and trigger the mannose trimming activity of ER degradation to correct misfolded proteins (10). In addition, TXNDC5 also plays a molecular chaperone role and act synergistically with HSC70 to promote inflammation through NF-κB signal transduction (11). The association between TXNDC5 and disease susceptibility has been extensively reported, and multiple SNP across the TXNDC5 locus are closely associated with disease development ( Table 1 ). In this review, we focus on the role of TXNDC5 in various diseases and discuss possible TXNDC5 applications for “TXNDC5-related diseases” particularly cancer, rheumatoid and fibrotic diseases.

TXNDC5 is a special member of the PDI family. 40 years ago, it was the first-discovered dithiol-disulfide oxidoreductase, and it is capable of reducing, oxidizing and isomerizing disulfide bonds (17). PDI family proteins consist of  four Trx-like structural domains (a, b, b′ and a′) located at the N-terminus and an additional α-helix c structural domain at the C-terminus (18). Together, they form a highly conserved U-shaped structure (19), with each domain connected by an unusually long flexible loop (20). The a and a′ structural domains are redox active due to the Cys-Gly-His-Cys motif and can act synergistically to promote the formation of natural disulfide bonds through the two oxidation sites (20). The b and b′ structural domains lack the Cys-Gly-His-Cys motif, leading to loss of redox activity. However, they are the main substrate binding sites (21–23) and can bind to different substrates through conformational changes (22, 24, 25) ( Figures 1A, B ). Unlike a prototypical PDI protein, TXNDC5 is a rare PDI containing the conserved APWCGHC thioredoxin domain but no b-structural domain (2, 18, 26). The C-terminus of TXNDC5 protein has an endoplasmic reticulum retention signal (KDEL), which is responsible for protein localization to the endoplasmic reticulum. TXNDC5 consists of three redox-like Trx domains (Trx1, Trx2 and Trx3), which form a clover-like structure (25). Each isolated Trx-like structural domain can rapidly import disulfide bonds independently and in a disorderly manner at the same rate as native TXNDC5 without selectivity (18, 27) ( Figures 1C, D ). Each Trx domain contains a CGHC motif as the catalytic domain for PDI activity. In contrast, PDI introduces natural disulfide bonds in an orderly manner through the synergistic action of two redox active sites and selectively proofreads unnatural disulfide bonds. TXNDC5 promote the formation and folding of disulfide bonds through the CxxC motif to enhance protein stability (6, 28). Moreover, TXNDC5 generates H₂O₂ through interaction with PDI endoplasmic reticulum oxidoreductase 1α (Ero1α) to participate in the catalytic oxidation reaction between peroxisomal protein 4 (prx4) and TXNDC5, thereby accelerating protein folding (29). Prx4 is typical of the 2-Cys Prx family (30, 31) and forms a homodecamer within which each dimer constitutes a key functional unit (32, 33). Sato Y et al. also demonstrated that TXNDC5 and other PDI family members can collaborate in peroxiredoxin 4-driven oxidative protein folding to increase the rate and fidelity of oxidized protein folding (27).

Sepsis is a fatal immune disorder (34, 35), excessive immune responses often result in systemic hypoperfusion, tissue hypoxia, and ultimately organ dysfunction (36, 37). Sepsis triggers the production of multiple pro-inflammatory and anti-inflammatory factors (38). Increased release of pro-inflammatory cytokines leads to dysregulated immune responses (39). Multiple pro- and anti-inflammatory factors including TNF-α, IL-1, IL-6 IL-8, IL-12, interferon (INF)-γ, granulocyte colony-stimulating factor (G-CSF), and the anti-inflammatory cytokine IL-10. Among them, TNF-α and IL-1 are considered to be the main pro-inflammatory factors (40–42). TNF-α activates inflammatory cytokines encoded by the NF-κB signaling pathway, adhesion molecules, gene expression of prostaglandin-synthesizing pathway enzymes, and induction of nitric oxide synthase (iNOS), which activates endothelial cells and leukocytes and exacerbates inflammatory responses (43–47). TXNDC5 was found to be upregulated in lipopolysaccharide (LPS) induced sepsis. Further research has found that inhibition of TXNDC5 attenuated-induced sepsis by suppressing the NF-κB signaling pathway. Moreover, knockdown of TXNDC5 effectively inhibited LPS-induced upregulation of pro-inflammatory cytokines (TNFα, IFN-γ, IL-12, IL-6, and MCP-1) and facilitated the production of the anti-inflammatory cytokine IL-10 (48).

In the development of rheumatoid arthritis (RA), TNF-α, IL-1, IL-6, IL-2 and many other inflammatory factors mediate the inflammatory response (49–52). TXNDC5 can also regulate a variety of cytokines to promote the development of the disease. Wang et al. found that in the presence of LPS, the NF-κB signaling pathway was activated by various pro-inflammatory factors such as IL-6, IL-8 and TNF-α, then induced the expression of TXNDC5, in turn, high expression of TXNDC5 can promote the production of pro-inflammatory factors such as IL-6, IL-8 and TNF-α (11); miR-573 can alleviate inflammation by enhancing the expression of TXNDC5, which in turn inhibits the expression of factors such as toll like receptor 2 (TLR2) and epidermal growth factor receptor (EGFR) (53). Highly expressed TXNDC5 can promote RA by inhibiting C-X-C motif chemokine ligand 10 (CXCL10) (54).

Inflammation often induces fibroblast recruitment and fibrosis, and several inflammatory factors, including TGF-β, IL-13, CD4, have been identified as triggers of fibrosis (55). For example, the pro-inflammatory cytokine interleukin 17A (IL-17A) induces fibrosis in the lungs, liver, kidneys, heart, and skin (56–61). IL-13 selectively induces and activates TGF-β in macrophages to promote fibrosis and promotes fibrosis independently of TGF-β by directly targeting stromal and parenchymal cells (62–64). TXNDC5 plays a critical role of endoplasmic reticulum protein disulfide isomerase (PDI) activity in TGFβ- mediated tissue fibrosis. TGFβ upregulates TXNDC5 by increasing ER stress levels and activating transcription factor 6 (ATF6)-mediated transcriptional regulation. Increased TXNDC5 lead to organ fibrosis by promoting myofibroblasts activation and excessive accumulation of extracellular matrix (ECM) proteins. Highly expressed TXNDC5 contributes to cardiac fibrosis (CF) by promoting ECM protein folding (65). Upregulated TXNDC5 can enhance TGFβ1 signaling by promoting the folding and stabilization of TGFBR1 in lung, leads to pulmonary fibrosis (PF) (66). TXNDC5 triggers renal fibrosis (RF) through enhancing TGF-β signaling pathway in renal fibroblasts (67). TXNDC5 promotes hepatic stellate cell activity and ECM through JNK and STAT3 signaling, thereby causing liver fibrosis (LF) (68). In conclusion, the TGFβ-ATF6-TXNDC5 signaling axis highlights the role of TXNDC5 in fiber formation during the development of fibrosis in heart, lung, kidney and liver organs (69).

TXNDC5 is involved in the tumorigenesis and progression by participating in inflammatory response. Multiple studies demonstrates that inflammation is closely relevant to the onset and progression of cancers (70–73). Specifically, chronic inflammation is involved in immunosuppression, acute inflammation induces cancer cell death via antitumor immunity, and the inflammatory response is also involved in anticancer therapies (74–76). For instance, TNF-α and IL-1β can play an important role in the occurrence of colorectal cancer through increasing the Toll-IL-1 receptor signaling (77). IL-17 produced by γδ T cells plays a key role in breast cancer metastasis (78). Additionally, TXNDC5 promotes cancer progression by regulating various inflammatory factors. TXNDC5 induces rhabdomyosarcoma proliferation survival and migration by regulating interleukin-24 (IL-24) (79), which has a wide range of anticancer activities and gradually be used in clinical therapy (80–82). TXNDC5 can also contributes to abnormal angiogenesis in cervical cancer by regulating inflammatory factor receptor expression of SERPINF1 and TRAF1, which can activate the NF-κB signaling in inflammatory environments (12, 83, 84). In conclusion, the insights have the potential to open new avenues in cancer treatment by targeting TXNDC5 to control aberrant inflammatory responses.

In conclusion, TXNDC5 directly or indirectly regulates inflammatory factors and promotes inflammatory responses ( Figure 2 ).

RA is a systemic autoimmune disease characterized by the proliferation of synovial fibroblasts (SFs), which produce a variety of proteases and inflammatory factors that destroy bone and cartilage (85). In the early stages of RA, the immune system is activated and immune cells (Dendritic cells, T cells and B cells) (86, 87) infiltrate joint tissues, leading to intra-articular hyperplasia and thus inducing synovial hypoxia and hypoperfusion (88). Furthermore, hypoxia induces the overexpression of TXNDC5. Chang et al. found that the expression of TXNDC5 is high in the synovial tissue and blood of RA patients by immunohistochemistry and western blotting (13, 89). Nine SNPs located in the TXNDC5 gene (rs1225936, rs1225938, rs2743992, rs372578, rs408014, rs41302895, rs443861, rs9392189, rs9505298) were found to be closely associated with RA susceptibility (14). Subsequently, Wang et al. found that hypoxia induced TXNDC5 overexpression in the synovial tissues of RA patients, which stimulated synovial fibroblasts to produce adiponectin (ADP). ADP subsequently stimulated synovial fibroblasts secrete cytokines and chemokines to promote inflammation, leading to RA (90). Through further studies, Wang et al. found that increased expression of TXNDC5, toll like receptor 2 (TLR2) and epidermal growth factor receptor (EGFR) could be suppressed by enhancing miR-573 expression during TXNDC5-induced RA, thereby alleviating inflammation (53). Meanwhile, Wang et al. revealed that the expression of TXNDC5 can be upregulated in response to inflammatory factors (LPS, TNF-α and IL-6) and under the control of NF-κB signaling. They found that heat shock cognate 70 protein (HSC70) forms a complex with TXNDC5 in the cytoplasm and their directly interaction can be strengthened in the presence of LPS, TNF-α and IL-6. Further research indicated that LPS stimulation is a key point in IκBβ nuclear translocation and subsequent NF-κB activation. HSC70 activates NF-κB signaling by destabilizing IκBβ protein in the absence of LPS or promoting its nuclear translocation in the presence of LPS. In the nucleus, newly synthesized IκBβ is in a quiescent statement and the NF-κB signaling is activated. Thus, TXNDC5 plays a pro-inflammatory role in RASFs by potentiating the effects of HSC70/IκBβ-mediated NF-κB signaling (11). Thus, the TXNDC5/HSC70-mediated inflammatory pathway forms a vicious circle in the progression of RA, and the two complement each other to play an important role in the RA process. Wang et al. also found that TXNDC5 could promote RA by upregulating TNF-α, IL-1α, IL-1β, and IL-17 (90). Xu et al. found that TXNDC5 overexpression inhibited CXCL10 and tumor necrosis factor-related apoptosis-inducing ligand TNF superfamily member 10 (TRAIL) expression, further contributing to the abnormal proliferation, apoptosis and angiogenesis of RASFs (54). Li et al. asserted that TXNDC5 induces insulin resistance and increases the risk of diabetes mellitus (DM) by inhibiting the expression of insulin-like growth factor binding protein-1 (IGFBP1) (91). The onset and progression of DM are closely related to systemic inflammation and insulin resistance, which is a state of impaired glucose metabolism and insulin dysfunction (92). It was reported that most patients with RA are insulin resistant (93–97). These studies suggested that there is a close connection between RA and DM. The study conducted by Alexander et al. revealed that the levels of fasting glucose are increased in 9 individuals with loss-of-function (LOF) variation in TXNDC5, indicating TXNDC5 can be identified as a potential determinant of type 1 diabetes risk (98).

In conclusion, the above studies regarding RA revealed the important facilitating role of TXNDC5 in RA progression and provide a new therapeutic target for the future treatment of RA ( Figure 3 ).

A growing body of data suggests a strong link between TXNDC5 and fibrotic diseases. TXNDC5 was found to be highly expressed in multiple fibrotic diseases, and TXNDC5 is a key pathogenic factor in multiple organ fibrotic diseases. In 2018, Shih et al. used RNA sequencing and gene co-expression network analysis to analyze data from failing human hearts, and found that TXNDC5 was highly upregulated in failing human left ventricular (LVs) (65). Highly expressed TXNDC5 can promote ECM enrichment to induce myocardial fibrosis by increasing NOX4-derived ROS and activating redox-sensitive JNK signaling. CF can lead to cardiac structural and functional remodeling, triggering diastolic dysfunction (99, 100) and consequently heart failure (HF). Increased levels of TXNDC5 expression further enhance the excessive accumulation of myofibroblasts and ECM proteins, leading to CF (65). Suppress the expression of TXNDC5 therefore provides a new therapeutic target for the treatment of CF, in contrast to traditional therapeutic modalities, including angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARBs) and mineralocorticoid receptor antagonist (MRA) (101–103). Targeting TXNDC5 does not limit the slowing of CF due to lower blood pressure. Moreover, inhibiting TXNDC5 expression can limit CF progression by silencing TGF-β1, thus attenuating fibroblast activation, ECM enrichment (65, 104, 105) and evading hepatotoxicity (106). In summary, silencing TXNDC5 provides new therapeutic strategies to alleviate CF and prevent HF.

In 2020, Lee et al. found that TXNDC5 was highly upregulated in lung tissue from patients with idiopathic pulmonary fibrosis and a bleomycin (BLM)-induced PF mouse models (66). TGF-β and TGFBR2 binding activates the TGFBR1/ER stress/ATF6 transcriptional pathway to drive TXNDC5 enrichment in lung fibroblasts, which in turn induces fibroblast hyperactivation, proliferation, and ECM enrichment through activation of TGF-β classical (SMAD3) (107) and nonclassical (JNK, ERK, PI3K, p38, MAPK) signaling (108), leading to PF. Suppress the TGF-β pathway represents an attractive approach to treat pulmonary fibrosis, but extensive inhibition of TGF-β leads to hepatotoxicity (109) and cardiotoxicity (110, 111); targeting knockdown of TGF-β1 causes interstitial pneumonia and systemic perivascular inflammation (112, 113); and targeting inhibition of TGFBR1 promotes impaired alveolar and epithelial cell production (114). TGF-β expression is necessary for lung organogenesis and homeostasis in vivo (115), therefore, direct down regulation of TGF-β rarely reaches the early clinical trial stage (109). However, compared with TGF-β, inhibit the expression of TXNDC5 showed no significant adverse effects.

Chen et al. Microarray data from renal biopsy specimens from CKD patients were analyzed and increased renal TXNDC5 expression was verified using gene knockout, flow cytometry, and immunohistochemistry. This study experimentally hypothesized to be under the control of the TGF-β1/ATF6/TXNDC5/TGFBR1 signaling axis, resulting in the enhancement of the folding and stability of TGFBR1. The signaling pathway leads to the amplification of TGF-β1 signaling and a series of renal fibrotic responses (67). Studies have shown that inflammation, tubular injury and other factors increase pro-fibrotic and inflammatory factors, inflammatory cells in large amounts, including TGF-β and macrophages (116). TGF-β is a key factor in the development of RF (117). Increasing expression of TGF-β drives fibroblast activation into collagen-secreting myofibroblasts (118–120), characterized by α-smooth muscle actin (αSMA) expression and excessive ECM deposition, leading to abnormal renal structure (121). In the process of treating RF, Chen et al. found that TXNDC5 deletion effectively ameliorated the development and progression of RF induced by various injuries in mice (67), providing a new and effective method for treating RF.

Hung et al. studied liver fibrosis (LF) and validated that the TGFβ/ATF6/TXNDC5/JNK/STAT3 signaling axis, suggesting that TXNDC5 plays a key role in the formation of LF (68). LF is generally caused by chronic liver injury (122), such as viral infections, nonalcoholic steatohepatitis (NASH), alcohol consumption (AC) and biliary obstructive disease (123, 124). Chronic hepatocellular injury could lead to epithelial/endothelial barrier damage, the release of inflammatory cytokines and the agglomeration of inflammatory cells followed by the secretion of profibrotic cytokines. Hepatic stellate cells (HSC) are activated and transformed into myofibroblasts, which leading to ECM enrichment, fibrous septa formation and regenerative nodules (124, 125). The activation of hepatic stellate cells into myofibroblast-like cells is the central link in the development of LF (126). Therefore, therapies that reduce HSC activation and ECM accumulation have become the mainstay of treatment for LF. TXNDC5 activates HSC through reactive oxygen species (ROS)-dependent JNK signaling; TXNDC5 also enables HSCs to avoid apoptosis via STAT3 signaling, leading to the enrichment of activated HSCs and excessive fibrotic in the liver. Inhibition of the catalytic function of TXNDC5 abrogates JNK and STAT3 activation, leading to downstream fibrotic responses (68). Silencing TXNDC5 reduces liver fibrosis in mice (127). Targeting TXNDC5 in HSCs reduces LF through limiting HSC cell activation by inhibition of noncanonical TGF-β signaling.

In summary, TXNDC5 is associated with key factors that promote the development of organ fibrosis. Targeting TXNDC5 deletion may be a potential new therapeutic strategy to improve fibrotic disease ( Figure 4 , Table 2 ).

It is well known that TXNDC5 is regulated by hypoxia (3), which induces vasoconstriction and coronary arteriosclerosis. Camargo et al. reported that TXNDC5 promotes the expression of proangiogenic proteases by regulating AP-1-dependent gene expression and induces angiogenesis in response to TNF-α (8). Yeh et al. revealed that TXNDC5 promotes atherosclerosis in vivo. Mechanically, TXNDC5 induces ubiquitination and proteasome-mediated degradation of HSF1, destabilizes eNOS protein by inhibiting HSP90 (148). Their further studies found that TXNDC5 deletion in vascular endothelium result in increased eNOS protein and reduced atherosclerosis in apoE ^−/− mice. Meanwhile, Kuhlencordt et al. found that atherosclerosis, aortic aneurysm formation and ischemic heart disease are accelerated in apoE/eNOS double knockout mice (149). These above findings indicates that TXNDC5 may lead to vascular diseases through regulating apoE and eNOS.

Holmgren et al. recently found that loss-of-function mutations in TXNDC5 may prevent key peptides from functioning properly, thus causing insulin hypersecretion (150). This resulted in insufficient insulin secretion. Subsequently, Alexander et al. showed that TXNDC5 could catalyze the reduction of insulin disulfide bonds and weaken the binding activity of insulin to the insulin receptor, thus causing abnormalities in glucose tolerance in the body, revealing an important role for TXNDC5 in promoting the development of diabetes (98). Recently, Li et al. found that high expression of TXNDC5 inhibited the expression of IGFBP1 to induce insulin resistance, increasing the risk of developing DM (91).

Ramírez et al. found that the severity of fatty liver induced by apolipoprotein E (ApoE) knockout was negatively correlated with the levels of TXNDC5 protein and mRNA. Their further study revealed that the expression of TXNDC5 reflected squalene’s anti-lipotropic properties and sensitivity to lipid accumulation (151). Karatas et al. found that four members of the PDI family (TXNDC5, PDIA4, PDIA3 and P4HB) were specifically upregulated in adult ZZ-AATD-mediated liver disease by studying hepatocyte function in patients with ZZ-type α1-antitrypsin deficiency (152). In the mechanism of interferon-stimulated gene 15 (ISG15)-induced hepatitis C virus (HCV) infection, ISG15 may promote HCV replication by regulating TXNDC5 (153–155).

Kim et al. found a correlation between TXNDC5 and skin aging by immunohistochemical assay and qRT−PCR in the skin tissues of 20 patients (156). In addition, TXNDC5 expression was higher in peripheral blood mononuclear cells in young adults than in older adults, suggesting that altered TXNDC5 expression may be associated with endothelial cell apoptosis (157).

In addition, certain SNP loci of TXNDC5 are closely associated with disease susceptibility. In a Korean population, three exonic SNPs (rs1043784, rs7764128 and rs8643) in TXNDC5 were found to be positively associated with nonsegmental vitiligo (NSV) (15). A SNP (rs13873) in the TXNDC5 gene and haplotype rs1225934-rs13873 in BMP6-TXNDC5 play a role in the selective impairment of persistent attention disorder in schizophrenia (16). The TXNDC5-related SNP (rs13196892: TXNDC5 | MUTED) that may be associated with human age was first identified in a study exploring female menopause/age-related factors (158).

In addition, TXNDC5 may be a predictive marker for histone deacetylase inhibitor (HDACI) resistance in cutaneous T-cell lymphoma during drug treatment of the disease (159), a predictive marker for resistance to bortezomib in refractory/relapsed multiple myeloma (160), a regulatory target of simvastatin to enhance docetaxel-induced cytotoxicity in human prostate cancer cells (161) and may be a key factor in the antioxidant effect of statins. Atorvastatin inhibits ROS production and Nox2 activity by promoting the membrane translocation of TXNDC5 in lipid rafts and enhancing the colocalization of TXNDC5 and Nox2, thus exerting antioxidant effects (162). Moreover, direct B lymphocyte LS-TA of TXNDC5 is an early biomarker of vaccine response in novel coronavirus pneumonia (COVID-19) (163).

In summary, TXNDC5 is expected to serve as a target for gene or drug therapy in an effort to change the trajectories of the aforementioned diseases.

TXNDC5, a member of the PDI protein family, is mainly found in tissues such as the brain, spleen, lung, liver, kidney, pancreas and testis. TXNDC5 consists of three redox-like Trx structural domains, each of them contains a CGHC motif that acts as an active catalytic structural domain for PDI activity, thereby regulating the rate of disulfide bond formation, isomerization and degradation of target proteins, thus altering the protein conformation and activity to improve protein stability. High expression of TXNDC5 is a key factor in the development of inflammation, cancer, rheumatoid arthritis, organ fibrosis, diabetes and other diseases.

In sepsis, RA and many other inflammatory diseases, TXNDC5 mediates the expression of a variety of inflammatory factors and receptors, which promotes the inflammatory response that leads to disease.

In fibrotic diseases, TXNDC5 acts as a mediator of TGF-ß signaling and amplifies TGF-ß induced fibrotic responses through its PDI activity to induce fibroblast activation, proliferation, and ECM production, inducing fibrosis in multiple organs such as the heart, lungs, kidneys, and liver.

In cancer, the SNPs in TXNDC5 gene are significantly associated with genetic susceptibility to a variety of cancers, including cervical cancer, hepatocellular carcinoma, liver cancer and esophageal cancer. Increased TXNDC5 expression can mediate neovascularization and promote cancer cell proliferation, invasion and metastasis.

In addition, TXNDC5 is strongly associated with a variety of diseases, such as diabetes, fatty liver, schizophrenia, and NSV.

Therefore, targeting TXNDC5 provides a powerful new tool for disease diagnosis and treatment. However, the specific roles and mechanisms of TXNDC5 in different diseases are not yet fully understood, and large-scale clinical trials are needed to validate the mechanism of TXNDC5 in different diseases as well as targeted therapies in the future.

MJ: Writing – original draft. YZ: Writing – review & editing. XS: Conceptualization, Funding acquisition, Supervision, Writing – review & editing. BX: Conceptualization, Funding acquisition, Supervision, Writing – review & editing.