The mutations in SLC4A1 result in hereditary spherocytosis (HS) or South East Asian ovalocytosis (SAO) [7]. Patients with HS have manifestations such as anemia and jaundice [100]. The disruption of erythrocyte deformability in patients with HS is the main pathological mechanism of HS. The reported mutation sites of SLC4A1 appear mostly in exons.

Mutations in SLC4A1 also can lead to dRTA [101]. In the absence of SLC4A1 activity, HCO₃⁻ and Cl⁻ will not be transported via SLC4A1, which leads to reduced HCO₃⁻ concentration in the renal interstitium and retained Cl⁻ in the renal tubule [102]. Therefore, patients with dRTA are characterized by hyperchloremic metabolic acidosis, accompanied by hypokalemia. Patients during adolescence are manifested by delayed growth, rickets, kidney stones, and calcium deposits [103]. The disease is inherited through the pattern of autosomal dominant (AD) and autosomal recessive (AR) [104]. Patients with AD dRTA have no disease symptoms until adolescence or adulthood, whereas patients with AR dRTA experience severe symptoms of disease that initially develop during childhood [104]. Clinical manifestations and laboratory tests, such as the short ammonium chloride loading test, can provide the initial evidence for the diagnosis of dRTA. Furthermore, the diagnosis can be validated by genetic analysis [102]. The high-resolution melting (HRM) method can be used as molecular diagnostic tool for AR dRTA associated with SLC4A1 mutations [104]. The effectiveness of HRM has the advantages of 100% convenience and rapidness in screening DNA specimens with the SLC4A1 mutation. Nevertheless, HRM has not been applied to the diagnosis of the SLC4A1 mutation in DNA specimens. In addition, PCR-RFLP and direct DNA sequencing are the conventional approaches for the analysis of the disease mutated by SLC4A1 and suggested to be used for confirming suspicious cases [104]. Clinical therapy for dRTA includes correcting metabolic acidosis and avoiding complications. Due to the reduced concentration of potassium ions, potassium-containing preparations should be considered [5]. As dRTA can lead to nephrocalcinosis, the therapeutic strategy of replacing the kidney is essential if the disease develops to chronic renal disease and can progress to end-stage renal disease [102].

The changes in the balance of tyrosine kinase and phosphatase activities could alter the expression of SLC4A1 [83]. Oxidative stress (OS) can induce tyrosine phosphorylation of SLC4A1 and cause membrane destabilization of red blood cells. It can also impact the binding of SLC4A1 and spectrin and actin via the ankyrin bridge, as well as the interaction of SLC4A1 and hemoglobin. OS can activate the posttranslational modification in the Nt of SLC4A1, inhibit the combination of the spectrin–actin cellular skeleton, and increase the deformability of erythrocytes [8]. The impact that ROS have on erythrocytes is shown in Figure 3. Since tyr-P levels of SLC4A1 are normally stable but changes under the influence of OS-related diseases, SLC4A1 tyr-P levels can be applied to analyze the functional state of red blood cells [105]. It is notable that SLC4A1 modifications associated with OS participate in the pathology of aging [106], diabetes mellitus [107], and inflammatory diseases like endometriosis [105]. Due to the ubiquitous expression of SLC4A1 in the human body, such as the brain and lymphocytes, it can be regarded as a marker for post-translational modification during ageing [8].

Meniere’s disease (MD) is an inner ear disorder, and its pathophysiology is characterized by endolymphatic hydrops. The diagnosis of the disease is based on clinical history and examination result [108]. SLC4A1 has been demonstrated to downregulate significantly in MD and acts as an important protective factor for the disease [109]. Nevertheless, the mechanism remains unclear.

Unexplained recurrent pregnancy loss (URPL) occurs during pregnancy and is accompanied by immune dysfunction. The disease involves a complex network of cytokines. CXCL-8 can regulate the release of inflammatory cytokines. The NF-κB signaling pathway is important for the release of cytokines in the downstream signaling pathways of inflammatory factors as well. Lnc-SLC4A1-1 can interplay with NF-κB to mediate the upregulation of CXCL8, which initiates inflammation. This process may lead to apoptosis and the migration of trophoblasts, resulting in URPL [110]. This provides the possibility of finding new markers for the diagnosis and treatment of this disease. Furthermore, the Lnc-SLC4A1-1/H3K27ac/NF-κB pathway may be an underlying mechanism to mediate the anti-tumor effect of physcion 8-O-β-glucopyranoside treatment. Therefore, this signal pathway may be a possible strategy for treating endometrial cancer [111].

Acute lung injury (ALI) is a disease characterized by tissue damage leading to pulmonary epithelial dysfunction and macrophage activation [112]. Activation of the NF-κB signaling pathway leads to the development of ALI. Inhibition of this signaling pathway has clinical value for the treatment of ALI [112]. MiR-1249–5p can improve ALI by targeting and downregulating SLC4A1, which is postulated to inhibit the NF-κB signaling pathway [112].

Patients with pulmonary arterial hypertension (PAH) manifest dyspnea on exertion, fatigue, edema, palpitation, and dizziness. Vascular remodeling can increase resistance in pulmonary vessels, which leads to the increase of pulmonary artery pressure. The diagnosis of pulmonary hypertension requires right heart catheterization to assess hemodynamic status. Furthermore, an ultrasound electrocardiogram is a good test item. SLC4A1 can be a biomarker of this disease, which can represent as a higher activation of some immune cells in their peripheral blood [113].

The dysfunction of SLC4A2 participates in the pathogenesis of primary biliary cholangitis (PBC) that is a chronic, biliary obstructive, and autoimmune disease. SLC4A2 deficiency can change the pH balance of immune cells, resulting in immune disorders in PBC patients [114]. The promoter region of the SLC4A2 gene is found to be highly methylated in the peripheral blood mononuclear cells of PBC patients. Methylation of CpG cytosines prevents DNA-binding proteins, resulting in transcriptional inactivation. Therefore, the mRNA produced by SLC4A2 is reduced in liver and lymphocytes of patients [114]. This process leads to the downregulated expression of SLC4A2 [115]. As the expression of SLC4A2 is reduced, the biliary HCO₃⁻ umbrella is broken. Bile salts enter cholangiocytes, which facilitate the ROS production and induce inflammation in primary biliary cholangitis [116]. The deficiency of SLC4A2 in PBC patients would make biliary cells more immunogenic and vulnerable to autoimmune injury, leading to immune disorders [115]. Chronic elevation of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total bilirubin with or without specific PBC clinical manifestations of pruritus and fatigue should be suspected of PBC [114]. If the disease is not treated timely, quite a few complications, such as liver failure and death, can be caused [117]. Ursodeoxycholic acid (UDCA) has been widely demonstrated to improve the clinical outcomes of PBC [118]. The drug could restore the expression and level of SLC4A2. Through the interaction of hepatocyte nuclear factor 1 with the glucocorticoid receptor, the combination of UDCA with glucocorticoids is able to activate the promoter of SLC4A2 in human hepatocytes [114]. MiR-506 can bind to the 3′ untranslated region of SLC4A2 mRNA, prevent the translation of mRNA into protein, and impair the function of bicarbonate secretion in the biliary tract. MiR-506 is up-regulated in the biliary tract cells of PBC patients and is considered to be a therapeutic target for PBC [119].

Mutations in SLC4A2 can cause the occurrence of osteopetrosis [120]. The SLC4A2 mutation can affect the differentiation of osteoclasts [41]. As the differentiation process of osteoclasts is affected, the mineralized material of the bone matrix fails to dissolve, and bone mineral density can be increased. This can lead to the occurrence of osteogenesis. Mutations in SLC4A2 affect cysteine protease activity, leading to the formation of abnormal podosome bands [42]. The aberrant podosome bands can impair bone resorption, which leads to an osteoporotic phenotype. The dysfunction of SLC4A2 would also break the dynamic organization of osteoclasts to maintain acid-base balance [42] as well. Patients with osteopetrosis have fractures and stunted growth. The diagnosis of osteogenesis is mainly based on a bone imaging examination. In the absence of imaging studies, elevated concentrations of creatine kinase, BB isoenzymes, and tartrate-resistant acid phosphatase are helpful in the diagnosis of autosomal dominant osteopetrosis (ADO). Genetic testing can be used to detect and distinguish different subtypes of osteoporosis [121]. As SLC4A2 plays a role in forming the actin rings of osteoclasts, it is considered a pathogenic gene to treat periprosthesis osteolysis. DIDS, which blocks SLC4A2 expression, has a positive effect on the reduction of the region that resorbs the bone, providing plausible evidence for its role in the therapeutic strategy of osteoclastic-associated osteolytic diseases [122].

The expression of SLC4A2 was found to be regulated in quite a few cancers. It was upregulated in the esophageal squamous cell carcinoma (ESCC), hepatocellular carcinoma [123], and colon tumor tissue, but downregulated in the gastric cancer (GC) cells [124]. In ESCC, the decreased SLC4A2 expression facilitates intracellular alkalinization, which promotes cancer cell metabolism [125] and is correlated with a poor prognosis [126]. Additionally, SLC4A2 was correlated with the proliferation [127] and migration [128] of the hepatoma cell. However, whether SLC4A2 affects the other biological behaviors of liver cancer requires further research. As the inhibition of SLC4A2 expression can decrease the proliferation of cancer cells, it may have a function in promoting colorectal cell growth. The expression of SLC4A2 can be inhibited by gastrin, leading to the inhibition of cancer proliferation [129]. p16 can bind with SLC4A1 and SLC4A2. The combination of p16 and SLC4A1 can facilitate the degradation of SLC4A2 in GC cells. Its downregulation in GC cells is partly attributed to the mediation of the ubiquitin proteasome pathway [130]. SLC4A2 is stimulated by transcription factor early growth response 1 in a cholecystokinin B receptor-dependent manner. The combination of tastuzumab and gastrin inhibits human epidermal growth factor receptor 2-negative GC cells, thereby inhibiting the complex of SLC4A1 and pl6, which may upregulate the expression of SLC4A2 in GC tissues [131]. As SLC4A2 is correlated with the poor differentiation and prognosis of the ESCC, hepatocellular carcinoma [123], gastric cells [130], and colon cancer [129], it is considered an underlying target for diagnosing and treating these diseases.

There are quite a few studies suggesting that SLC4A3 is associated with heart disease. Short QT syndrome (SQTS) is an inherited disorder caused by a defect in potassium and calcium channels that leads to an abnormally short QT interval. Recently, it was reported that the mutation in SLC4A3 causes SQTS [132]. Inhibited activity of SLC4A3 can lead to increased intracellular pH and decreased concentration of intracellular Cl⁻. This can affect the activity of other channels expressed on the myocytes. For example, Kv7.1 channels (KCNQ1) are activated and L-type Ca²⁺ channels are inhibited. The process can contribute to repolarization. Furthermore, the reduction of intracellular chloride concentration can make its equilibrium potential more negative, thus increasing the inflow of chloride in the second stage and at the start of the third stage and reducing the time of action potential. In addition, chloride channels in cardiomyocytes are inhibited due to the decrease in intracellular Cl⁻ concentration. This may directly lead to the arrhythmia in SQTS. The most common clinical manifestation of SQTS is cardiac arrest. Other clinical manifestations include palpitations and syncope. An implantable cardioverter defibrillator is the first-line treatment for SQTS. Quinidine can prolong the QT interval and is effective in the treatment of SQTS, especially in those patients who have contraindications to defibrillators and are rejected [133]. Currently, the role of genetic testing in the diagnosis of SQTS has not been elucidated. It has been demonstrated that SLC4A3 should be incorporated into the genetic screening of patients with SQTS [134].

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmia disease that can cause sudden cardiac death. Similar to SQTS, genetic screening is widely used for this rare genetic disorder. SLC4A3 has an antidiastole value for diagnosing CPVT [135] as well.

In addition, the deficiency of SLC4A3 can lead to rapid decompensation, make heart failure occur more easily [136], and disturb normal cardiac function to react efficiently to acute stress [137].

Idiopathic generalized epilepsy (IGE) is an age-related, recurrent, generalized seizure with no obvious trigger, no detectable brain damage, and no metabolic disorder. Genetic factors play an important role in the etiology of IGE [51].

In the brain, the Ala867Asp variant in SLC4A3 is associated with epilepsy [51]. The variants are evidenced to lead to decreased SLC4A3 transport activity, resulting in abnormal intracellular pH and cell volume changes, which may facilitate neuronal hyperexcitability and seizures [138]. But the molecular basis for this effect has not been determined [139]. Patients with SLC4A3 deficiency present with the retinal pathological phenotype of most vitreoretinal degeneration [55].

Early stages of non-small cell lung cancer (NSCLC) can be classified by surgical pathology. The research indicates that detection of SLC4A1 and SLC4A3 can predict the prognosis in patients with the early stage of NSCLC [140]. Cells are capable of osmoregulation by activating a number of transporters. During cell transformation, ion channels become dysregulated. As SLC4A3 is involved in cellular transformation, it can be a good marker and an excellent therapeutic target for transformative diseases such as cancers [141].

Recessive mutations in SLC4A4-A lead to proximal renal tubule acidosis (pRTA) [6]. pRTA is an inherited disorder that is characterized by reduced HCO₃⁻ resorption in the proximal renal tubule. Due to the defect of HCO₃⁻ resorption, pRTA represents metabolic acidosis such as hypokalemia, normal anion-gap metabolic acidosis, and aciduria (pH < 5.5) [142]. As SLC4A4-A is expressed in other tissues like the nervous system, pRTA can also present with extrarenal manifestations such as developmental and intellectual disabilities, ocular defects such as cataracts and glaucoma, and dental defects [143].

SLC4A4-B can be linked to a primary headache, largely due to the dysregulation of brain local pH. To some extent, the reduction in SLC4A4-B activity may cause hemiplegic migraine in astrocytes, which is accompanied by a complex aura that includes a motor defect. Misfolded SLC4A4-B can cause abnormal NMD-mediated neuronal hyperactivity, which may be the pathogenesis of migraine in homozygotes [144].

SLC4A4 is located on chromosome 4 and indicates that it may be related to dental development. Additionally, it is also involved in the pH regulation of amelogenesis. SLC4A4 can be a candidate gene for amelogenesis imperfecta in human diseases [145].

Furthermore, SLC4A4 participates in the development of type 2 diabetes mellitus (T2DM), which is due to perturbation of the β cell’s transcriptional regulation. The abnormal regulation of glucose-stimulated insulin secretion (GSIS) is partly assigned to the mitochondrial dysfunction, which is a major constituent of β cell failure in T2DM. The increased SLC4A4 activity is associated with intracellular alkalinization in tumoral β cells [146]. The upregulated expression of SLC4A4 can lead to intracellular alkalinization and impair mitochondrial function, which contributes to β cell functional failure and glucose intolerance. Through inhibiting SLC4A4 with S0859, pH_i can be lowered and GSIS is enhanced in T2DM human islets. Thus, inhibition of SLC4A4 may be considered a potential strategy to counteract β cell failure in T2DM [147].

SLC4A4 participates in acute and chronic hypoxia along with ischemia [148] in neurons and glia, such as the interrupted supply of some significant substances like oxygen and glucose, as well as the impeded synthesis of ATP. These metabolic processes can eventually lead to extracellular acidosis. As the intracellular and extracellular environment is acidic during ischemia, SLC4A4 uses the electric potential of Na⁺ to fulfill the transport of Na⁺ and HCO₃⁻, thus regulating pH. During the reperfusion, while extracellular pH returns to normal and intracellular pH remains acidic, the pH gradient helps H⁺ extrusion [149]. NHEs, by means of extruding H⁺, provide the way for the entry of HCO₃⁻ through NBCs. As ATP synthesis is prevented and the activity of Na⁺/K⁺ ATPase decreases, the intracellular concentration of Na⁺ is increased, which induces cell depolarization and stimulates the abnormal release of excitatory amino acid transmitters. Due to the reversed transport of the Na⁺/Ca²⁺ exchanger, the intracellular concentration of Ca²⁺ increases and promotes a variety of calcium-activated cell damage processes [150].

Prostate cancer (PC) is a common disease that can affect men’s health, and its diagnosis and treatment are complex [151]. As circle RNA is found to have potential value for the diagnosis and treatment of diseases, hsa_circRNA_001587 is applied to the research. The experiment has indicated that increased activity of hsa_circRNA_001587 can upregulate the expression of SLC4A4, which curbs the neoplastic processes of PC through binding to miR-223. The hsa_circRNA_001587-miR-223-SLC4A4 axis plays a role in the development of PC [152]. Nevertheless, the tumorigenic mechanisms of PC require further research. Through the regulation of the AKT pathway, SLC4A4 can promote the progression of PC, and its inhibition can be an excellent therapeutic strategy for treating the disease [153].

SLC4A4 is evidenced to be the most abundant HCO₃⁻ transporter expressed in pancreatic ductal adenocarcinoma (PDAC) [154]. The low pH of the tumor microenvironment can lead to aberrant function of immune cells such as CD8+T cells and impact the efficacy of immune checkpoint inhibitors. Inhibition of SLC4A4 activity can increase the accumulation of bicarbonate in the extracellular space and reduce the secretion of lactate, thereby alleviating acidosis in the acidic tumor microenvironment. Inhibiting SLC4A4 is considered a possible remedy to improve immunoreaction, which inhibits tumor growth and metabolic processes. SLC4A4 can be a therapeutic target to tackle immunotherapy resistance and prolong survival in PDAC [154].

As the reduced expression of SLC4A4 in patients with colon adenocarcinoma is associated with lymph node invasion and distant metastasis, this gene is supposed to be a biomarker to predict the poor prognosis of patients [155].

According to transcriptome analysis, it is hypothesized that SLC4A5 activates a regulatory cascade and is composed of compensated HCO₃⁻ reuptake through other transporters that mediate the transport of Na⁺ and HCO₃⁻ (e.g., SLC4A7), thus causing increased Na⁺ absorption. This will increase blood pressure and lead to hypoaldosteronism, which explains the connection of the SLC4A5 locus to hypertension in humans from the perspective of molecular mechanism [156]. According to some studies, HCO₃⁻ transport mediated by SLC4A5 in the choroid plexus epithelium (CPE) is the major molecular mechanism to regulate the cerebrospinal fluid (CSF) during respiratory acidosis [157]. SLC4A5 is downregulated in Alzheimer’s disease and considered to be a candidate gene to produce CSF in AD. The altered expression of SLC4A5 can adversely impact the normal function of CSF secretion by impacting the carriage of electrolytes and water from CPE to CSF [156,158].

Genome-wide association studies discovered that a variant of SLC4A7 is associated with blood pressure [159]. SLC4A7 is related to hypertension due to vascular change. Mutations in SLC4A7 lead to mildly reduced blood pressure on the account of the altered vessels and the inhibition of NO synthase and Rho kinase [160]. Reduced endothelial NO production can result in downregulated arterial dilatation and mildly upregulated blood pressure. In addition, the loss of SLC4A7 activity causes reduced intracellular pH, thereby influencing local signals that regulate arterial dilatation and arterioconstriction. The depression of the Rho kinase signal channel is regarded as the potential mechanism of the changed vascular function. SLC4A7 may represent a new target, and its inhibition provides a new approach for treating cardiovascular disease.

The research on alcohol addiction demonstrated that the defective activity of SLC4A7 can elevate the consumption of alcohol and make the body more susceptible to sedation induced by alcohol. The underlying mechanism may be intracellular acidosis and decreased nerve excitability. Chronic alcohol consumption in mice reduces the expression of Slc4a7 in a positive feedback manner, suggesting that Slc4a7 plays an important role in regulating alcohol consumption and susceptibility to alcohol-induced sedation [161].

In addition, chronic acidosis is related to increased poisonousness mediated by glutamate, causing neurologic impairment. Acidosis may cause ATP consumption and a depolarized membrane, which eliminates Mg²⁺. N-methyl-D-aspartate receptors are known to be activated to trigger apoptosis and lead to cytotoxicity under no or decreased Mg²⁺ concentrations. Therefore, neuronal death is further promoted to some extent [162]. Due to its significant function in neural damage, SLC4A7 may be considered a new neuroprotective target for brain damage induced by glutamate [163]. Mutation in SLC4A7 can lead to reduced locomotor activity, which may result from an alteration in exploratory behaviors or emotional ability. Furthermore, deficits in visual and acoustic faculty can impact affective and cognitive function [11]. The altered perception of sensory cues may impact animals’ capability to explore their environments for survival and adaptation. However, it has been studied that SLC4A7 displays few roles in motor ability [164].

SLC4A7 is revealed to upregulate in the carcinoma cell line in the presence of the MCF-7 Nt-truncated ErbB2 receptor (NErbB2). This overexpression increases carcinomas’ acid excretion ability and alleviates the acid load inside cells generated from glycolysis, thus regulating intracellular pH. It is postulated that SLC4A7 can impact breast carcinoma by acting as a modulator or a tyrosine kinase substrate through the development of carcinomas [165]. Furthermore, SLC4A7 can impact the progression of head and neck squamous cell carcinoma (HNSCC). Through the activation of the PI3K/AKT/mTOR signaling pathway, SLC4A7 contributes to the migration and invasion of HNSCC. The role of SLC4A7 in the PI3K/AKT/mTOR signaling pathway indicates that it can act as a predictive biomarker and therapeutic target in HNSCC [166].

The disruption of SLC4A10 can lead to epilepsy [9]. Due to the alteration of acid-base equilibrium, neuronal excitability is impacted. This can make epileptic phenotypes easier to develop. Additionally, SLC4A10 is hypothesized to function in the pathology of primary open-angle glaucoma (POAG). The clinical manifestation of POAG is chronic optic lesion and progressive loss of retinal ganglion cells, leading to specific visual field defects [167]. SLC4A10 participates in CSF production and can impact translaminar pressure [167]. A decrease in CSF pressure and increased Intraocular Pressure can cause an increased translaminar pressure difference, thus disturbing axoplasmic flow and induced retinal apoptosis.

Currently, it remains unclear whether SLC4A8 plays a role in the development of salt-dependent hypertension. Research indicates that SLC4A8 and SLC26A4 mediate the reabsorption of electrically neutral sodium chloride in renal cortical collecting ducts. This provides insights into the treatment of arterial hypertension and contributes to the understanding of the regulation of sodium and potassium homeostasis by cortical collecting ducts.

Mutations in the SLC4A11 gene get involved in corneal dystrophies, such as congenital hereditary endothelial dystrophy (CHED) [168], which is a rare corneal endothelial dysfunction. The most common cause of CHED is misfolded proteins that prevent the protein from maturing and trafficking to the plasma membrane. Other causes include oxidative stress due to misfolded proteins and compensatory changes in other gene products [169]. The endoplasmic reticulum (ER) is an organelle that recognizes misfolded proteins. When the formation rate of misfolded proteins reaches saturation, it can lead to ER stress [170]. ER stress occurs in CHED [171]. In addition, SLC4A11 was able to adhere to the descemet’s membrane. When this adhesion function is lost, it leads to the occurrence of CHED and Fuchs’ endothelial corneal dystrophy (FECD) [81]. FECD is a progressive, overt disease with the onset of symptoms in the 40th to 50th years of life. FECD can be affected by mutations in other genes, while CHED is only caused by mutations in SLC4A11 [81]. Due to its pathogenesis, it is proposed that correcting misfolding is an effective therapeutic strategy. Non-steroidal anti-inflammatory drugs can effectively treat some hereditary FECDs whose etiology has been identified by genetic testing [172]. Furthermore, a dysfunction of SLC4A11 can lead to the generation of mitochondrial ROS, which can damage the mitochondria and promote mitophagy. In the meantime, the function of lysosomes is destroyed and aberrant [171]. Research indicates that patients with CHED mutated by the homozygous SLC4A11 can develop Harboyan syndrome at a later age [173], which can lead to progressive sensorineural hearing loss.

Glutamine is known to be required by carcinomas proliferation [174], known as “glutamine-addicted” cancers. It can provide cells with essential substrates. SLC4A11 is significantly upregulated and seems to be a risk factor for ovarian carcinoma [175]. It has been found that increased SLC4A11 expression is related to the poor prognosis of colon cancer [176]. Experimental trails demonstrate that inhibiting the activity of SLC4A11 and glutaminase (GLS1) could have a very robust effect on disrupting glutamine-addicted cells.