Research progress on BTG2 in non‑tumor diseases (Review).

The B-cell translocation gene (BTG)/transducer of ERBB2 (TOB) protein family is a highly conserved group of regulatory proteins that consists of BTG1, BTG2/PC3/BTG anti-proliferation factor 2 (Tis21), BTG3/ANA, BTG4/PC3B, TOB1/TOB and TOB2 ( 1 ). The BTG domain, which consists of two distinctive subregions, Box A and Box B, is a highly conserved functional module shared by all members ( 2 ). These subregions mediate interactions with different transcriptional regulators and proteins involved in mRNA metabolism ( 3 ). The highly dynamic expression profile and precise molecular regulatory processes as an immediate early response gene make BTG2 distinctive within the BTG family. This establishes BTG2 as an essential quantitative threshold sensor for cellular stress responses and fate determination. Compared with other family members, BTG2 responds rapidly to DNA damage events, oncogene activation or growth signaling, facilitating quick intervention in cellular processes. At the molecular level, BTG2 only uses its conserved Box A and Box B domains to exert its non-catalytic adapter function. Based on upstream signal intensities, it competes stoichiometrically with the carbon catabolite repression 4-negative on TATA-less C-C motif chemokine receptor 4 (CCR4-NOT) deadenylation complex and protein arginine methyltransferase 1 (PRMT1) methyltransferase to mediate the quantitative redistribution of downstream mRNA stability and protein modification state. Because of its molecular design, BTG2 can coordinate binary destiny decisions between irreversible apoptosis and reversible cell cycle arrest by integrating stress magnitude and environmental cues in a manner comparable to an environmentally dependent resistor. BTG2 differs from other members of the family owing to its distinctive spatiotemporal sensitivity, signal integration capacity and plasticity. Within this family, BTG2 is one of the most extensively studied and functionally diverse core members because of its impact on stress response, DNA damage repair, signaling pathways and cell cycle regulation. Its mechanisms of action and pathophysiological relevance extend beyond the scope of tumor suppression ( 4 - 8 ). BTG2 belongs to the BTG/TOB antiproliferative protein family. The BTG2 gene is found on human chromosome 1q32 and encodes a protein containing 158 amino acids and a relative molecular mass of ~20 kDa ( 8 ). Its conserved BTG domain ( 9 ), which confers dual regulatory functions, is central to its basic molecular activity. First, by selectively attaching to the deadenylase CCR4-NOT transcription complex subunit 7 (CNOT7, also known as CAF1), a key linker protein in the mRNA degradation complex, it drives the deadenylation and degradation of target Mrna ( 10 ) and accelerates post-transcriptional regulation. Second, it accurately modifies the transcriptional activity of downstream genes as a transcriptional co-regulator by interacting with critical signaling molecules, such as p53 and Smad ( 11 , 12 ). The core biological functions of BTG2 are primarily reflected as the braking and directing of cell fate through these processes. It triggers the cell cycle to enter G1 phase arrest ( 5 , 13 ), which compels cells to stop proliferating while initiating differentiation-related processes ( 14 ). Consequently, BTG2 is essential for suppressing aberrant proliferation, promoting cell differentiation and maintaining tissue homeostasis. These characteristics position BTG2 as a pivotal molecular hub that regulates development, stress responses and the advancement of non-neoplastic diseases while establishing it as a crucial tumor suppressor. Research on BTG2 has traditionally focused on tumor biology ( 15 - 18 ) because of its central role in cell cycle arrest, cellular stress ( 19 ) and the DNA damage response ( 5 , 20 , 21 ), as well as BTG2 downregulation in various cancers and its evident tumor suppressor activity ( 22 - 25 ). However, the understanding of BTG2 is expanding. Research perspectives have steadily expanded from cancer to non-neoplastic disorders owing to advancements in genomics and the development of disease models. This former cell cycle gatekeeper has demonstrated surprising adaptability: BTG2 is expressed in organs, such as the spleen, thymus, lungs, stomach, large intestine and kidneys ( 26 - 28 ). Building upon our own previous research, BTG2 promotes podocyte injury in focal segmental glomerulosclerosis (FSGS) through a Smad3-dependent mechanism, including epithelial-mesenchymal transition (EMT) and fibrosis. The relationship between BTG2 and renal fibrosis is the subject of further investigation by the group. Furthermore, BTG2 is central to conditions such as fibrotic diseases ( 29 ), neurological diseases and cardiovascular disorders ( 30 ). Building on this, the present review extends its scope to explore the association between BTG2 and other fibrotic diseases. Non-oncological disorders are being investigated considering the earlier focus on oncology contexts. These results compel a reevaluation of the biological relevance of BTG2, suggesting that it may serve as a cellular homeostasis regulator implicated in pathophysiological events. This review aimed to systematically summarize the research progress on BTG2 in non-neoplastic diseases, emphasizing its molecular mechanisms and pathophysiological importance in fibrotic diseases, neurological disorders and cardiovascular diseases. This systematic literature review further intended to explore the translational medical impact and potential therapeutic strategies targeting the BTG2 signaling network to offer comprehensive theoretical references and novel insights into related research fields.

Apart from its function in liver fibrosis, BTG2 is widely expressed in the liver and contributes to various physiological and pathological processes ( 100 ). Under typical metabolic conditions, it influences hepatic defense against oxidative stress by activating the NFE2 like bZIP transcription factor 2 pathway ( 101 ). Additionally, it serves as a key component of the growth hormone pathway, working in tandem with YY1 and CREBH to promote hepatic gluconeogenesis and sustain glucose homeostasis ( 102 , 103 ). However, BTG2 exerts context-dependent dual effects in liver injury. For example, BTG2 downregulation impairs hepatic defense in hookworm infection ( 40 ). Conversely, its upregulation during IRI may exacerbate tissue damage ( 104 - 106 ). Likewise, a study using on recombinant AAV-based liver-targeted gene knockdown models have demonstrated BTG2 expression in Kupffer cells, hepatocytes and endothelial cells. BTG2 upregulation during IRI has been associated with inflammatory responses and tissue injury ( 107 ). Notably, the liver-specific knockdown of BTG2 reduces its mRNA and protein levels by >50% and confers protection during injury. Similar pro-inflammatory or pro-apoptotic effects have been observed in drug-induced liver injury (DILI), partial hepatectomy and aging liver ( 108 - 110 ). BTG2 upregulation may cause damage by modulating the TNF-α pathway, affecting immune cell function, participating in DNA damage responses ( 111 ) or promoting apoptosis. Furthermore, changes in intracellular metabolism and gene expression, including changes in BTG2, may facilitate the co-induction of specific DILI through incompatible bavachin and icariin in the presence of TNF-α ( 109 ). By contrast, elevated BTG2 expression protects macrophages in non-alcoholic fatty liver disease, exerting anti-inflammatory and antioxidant effects, thereby reducing lipid accumulation and inflammation ( 112 ). In summary, BTG2 functions as a critical regulator of hepatic stress responses, metabolic homeostasis and injury repair. Its protective and detrimental effects largely depend on the pathological context. BTG2 exhibits differential expression patterns and complex regulatory functions in pulmonary diseases, which demonstrate its context-dependent function in lung pathologies. BTG2 expression is upregulated in monocytes/macrophages in chronic obstructive pulmonary disease, which may promote pro-inflammatory reactions and contribute to disease progression, corroborating its potential as a biomarker ( 113 ). By contrast, the enhancer of zeste 2 polycomb repressive complex 2 subunit-forkhead box O3-miR-34b regulatory axis suppresses BTG2 expression in asthma, reducing BTG2 levels that promote inflammatory responses and disease development ( 114 ). BTG2 serves as one of three key exosome-associated biomarkers in obstructive sleep apnea (OSA), which has been associated with intermittent hypoxia and metabolic dysregulation. BTG2 expression is significantly decreased in patients with OSA, which correlates with immune-metabolic imbalance. Mechanistically, BTG2 regulates lipid metabolism by suppressing the STAT3 pathway and downregulating IL-6. Immune profiling further confirms a positive correlation between BTG2 expression and memory B cells and a negative correlation with CD56-bright natural killer cells. Furthermore, low BTG2 levels are related to a high risk of OSA ( 115 ). Collectively, these findings support a 'hypoxia-exosome-immune' triad mechanism where BTG2 regulates immune-metabolic homeostasis. In summary, BTG2 plays a substantial but diverse role in pulmonary inflammatory diseases, and its functional direction and regulatory networks vary across conditions. BTG2 is strongly associated with the pathogenesis of renal diseases. It primarily affects immune regulation, cellular stress response and kidney development. With a high centrality score and major regulatory roles that are probably associated with immune pathways, BTG2 may function as a hub gene and a pivotal gene in multi-layer regulatory networks in DN. BTG2 shows promise as a therapeutic target that warrants further investigation, together with other hub genes, such as JUN, CDK inhibitor 1B, VEGFA, phosphatase and tensin homolog, EGFR, MYC and tumor protein 53 ( 116 ). Apart from DN, BTG2 has diverse roles in other renal pathologies. For instance, in patients undergoing hemodialysis, a p53-dependent mechanism induces BTG2 expression in skeletal muscles, which reflects cellular responses to DNA damage and oxidative stress from the uremic environment ( 117 ). Notably, this p53-BTG2 regulatory axis is not exclusive to hemodialysis. It represents a wider, evolutionarily conserved stress-response pathway that has been implicated in various conditions, including malignancies, neurodegenerative diseases, cardiovascular disorders and metabolic disease, where p53 activation (triggered by genotoxic, oxidative or metabolic stress) in turn induces BTG2 expression. Furthermore, BTG2 expression can be modulated through p53-independent mechanisms, such as TGF-β/Smad signaling, MAPK pathways and Sp1/Sp3 transcription factors, highlighting the multifaceted signaling network that regulates BTG2 expression across tissues and diseases. BTG2 downregulation, likely regulated by miR-146a-5p, disrupts immune balance in idiopathic membranous nephropathy ( 118 ). In renal SCII, BTG2 serves as an NF-κB signaling-responsive gene and as a prognostic marker that mediates both inflammation and cellular stress. This role is critical in transplantation-related SCII, characterized by aberrant BTG2 activation in specific renal cell populations. This feature connects inflammatory signaling to cellular damage ( 119 ). Additionally, loss of BTG2 function - particularly in women - reduces nephron numbers and impairs salt-handling capacity in salt-sensitive renal injury, causing severe hypertension and proteinuria ( 120 ). Collectively, these findings emphasize the role of BTG2 in the pathophysiology of renal diseases, underscoring its potential as both a biomarker and a therapeutic target across renal conditions. BTG2 is among the four genes used to diagnose lupus nephritis (LN). However, BTG2 expression is high in the control group and significantly downregulated in the LN group. Further gene enrichment analysis highlights the role of BTG2 in biological processes, including phagocytosis regulation, viral infection defense, the activating transcription factor 6-mediated unfolded protein response, neuronal cell homeostasis maintenance and sodium ion transmembrane transport. Additionally, BTG2 is associated with the Toll-like receptor pathway. It has been hypothesized that upregulating BTG2 expression may inhibit the activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, thereby delaying LN progression ( 121 ). BTG2 plays context-dependent roles in the reproductive system. Elevated BTG2 expression has been associated with diminished potential of oocyte development during in vitro fertilization/intracytoplasmic sperm injection in granulosa cells, particularly in women with high antiMüllerian hormone levels ( 122 ). It serves as a cell cycle inhibitor in ovarian cell cultures ( 123 ). Conversely, high BTG2 expression correlates with greater oocyte retrieval and blastocyst formation rates in endometriosis-related infertility, highlighting its potential as a predictive biomarker ( 124 ). Additionally, BTG2 has been implicated in the immune microenvironment of patients with obese polyendocrine metabolic ovarian syndrome, indicating its contribution to disease pathogenesis ( 125 ). The BTG2 gene is central to both intervertebral disc degeneration (IDD) and musculoskeletal disorders. In IDD, BTG2 serves as a high-confidence biomarker that modulates extracellular matrix metabolism and immune responses, thus affecting degeneration ( 126 ). Hsa-miR-185-5p regulates BTG2 expression, which is downregulated in degenerated disc tissues ( 127 ). Additionally, BTG2 is involved in the ceRNA axis, such as the BTG2/hsa-miR-185-5p/SOCS3 network ( 126 , 127 ), thus serving as a therapeutic target. In musculoskeletal diseases, BTG2 has been associated with sarcopenia, skeletal muscle development, myoblast function and muscle aging. Furthermore, it serves as a diagnostic biomarker in sarcopenia, with elevated expression observed in cellular models. It influences disease progression by regulating muscle stem cell senescence ( 128 ). BTG2 has been identified as a critical gene for postnatal muscle growth in the Tianzhu white yak during skeletal muscle development and has functional correlations with genes, such as ankyrin repeat domain 2 ( 129 ). BTG2 overexpression suppresses myoblast proliferation while promoting differentiation, which is directly targeted by miR-103-3p ( 130 ). BTG2 is a possible treatment target in muscle aging because it induces muscle stem cell senescence, which has been associated with cumulative DNA damage ( 131 ). Collectively, BTG2 regulates essential cellular processes in the musculoskeletal system, influencing both disc integrity and muscle function. These processes include proliferation, differentiation, senescence and molecular signaling pathways. These roles underscore the potential of BTG2 as a biomarker and a therapeutic target for musculoskeletal conditions. BTG2 has been identified as one of the key genes that regulates immunity, inflammation and the cell cycle in a model of early-onset spinal curvature (EOS) combined with thoracic functional insufficiency syndrome (TIS) in pigs. Compared with the control group, the EOS + TIS model group demonstrated significantly downregulated BTG2 expression in lung tissue. Therefore, BTG2 may have a negative regulatory function in impaired lung development caused by EOS + TIS ( 132 ). BTG2 has been strongly associated with DNA damage ( 133 ), oxidative stress and aging pathways. In a study on ocular disease, BTG2 is activated in the retina of lens-induced myopic guinea pigs, where it promotes DNA damage and apoptosis, resulting in retinal thinning. By contrast, miR-92b-3p exerts protective effects by targeting and suppressing BTG2 expression ( 134 ). Concurrently, BTG2 is regulated by both LINC01136 and hypoxia-inducible factor-1α under hypoxic conditions; it inhibits the proliferation of retinal microvascular endothelial cells, which affects neovascularization-related pathological processes ( 135 ). MiR-202-3p targets and regulates BTG2 in vascular calcification, thus accelerating calcification progression ( 136 ). BTG2 serves as a cell senescence-related gene and a diagnostic biomarker in abdominal aortic aneurysm ( 137 ). In urticaria, it contributes to miRNA-mediated post-transcriptional dysregulation and inflammatory signaling ( 138 ). In aging models, long interspersed nuclear element-1 RNA regulates BTG2 expression, which has been associated with a disruption of heterochromatin homeostasis ( 139 ). Thus, BTG2 is central to non-neoplastic pathological processes, such as DNA damage, aging and metabolic diseases, where it regulates cell cycle, stress responses and metabolic processes ( Fig. 4 ). These findings offer novel directions for understanding the underlying mechanisms and targeted treatment of related conditions.

Originally discovered as an antiproliferative gene ( 8 ), BTG2 is now recognized as a key regulator of cellular adaptability across a wide spectrum of non-tumor diseases. Over the last 10 years, BTG2 has been identified as a context-sensitive integrator of signals that regulate cell-cycle control, apoptosis, differentiation, inflammatory activation and tissue remodeling rather than only a downstream stress-responsive molecule ( 140 , 141 ). BTG2 deficiency affects various disease states. In the nervous system, BTG2 deficiency impairs hippocampus-based learning and memory and decreases neurogenesis, indicating its function in neurodevelopment and cognition ( 142 ). In terms of metabolism, knockout mice have a higher body weight and lower insulin sensitivity, whereas their fibroblasts proliferate more rapidly and are resistant to p53-dependent cell cycle arrest ( 14 ). Notably, podocyte-specific BTG2 deletion in the kidneys markedly attenuates glomerulosclerosis and inhibits EMT, suggesting its pro-fibrotic role ( 34 ). This finding is contrary to its regulatory role in oral submucous fibrosis reported in another study ( 29 ). Furthermore, BTG2-deficient mouse models with inflammatory injury display unwarranted inflammatory responses, confirming its negative regulatory role in inflammation resolution. In contrast to other dual-function molecules, such as p53, NF-κB and TGF-β, BTG2 is unique because it is defined, in the context of signal transduction, as a non-catalytic, abundance-driven adapter node located at critical downstream signaling convergence sites. BTG2 functions solely through protein-protein interaction modules, whereas pleiotropic transcription factors, such as p53, NF-κB or TGF-β, decode upstream signals through intrinsic enzymatic activity or DNA-binding domains. Stoichiometric competition between several effectors, particularly the CNOT7/CCR4-NOT deadenylase complex and PRMT1 methyltransferase, controls its biological outputs by transforming graded upstream signals into a quantitative redistribution of molecular interactions. Thus, to coordinate binary cell fate decisions, BTG2 serves as a quantitative threshold sensor that combines stress intensity and environmental inputs. The dynamic interactome equilibrium formed by the cellular milieu ultimately determines its functional outcome rather than an intrinsic catalytic switch. One important insight from this review is that a fundamental protective ( Table I )-vs.-pathogenic ( Table II ) paradigm is insufficient to entirely understand BTG2. The possible mechanisms underlying its context-dependent roles are as follows. First, BTG2 consists of inherently disordered non-coding regions, and non-coding RNAs have substantially varied expression profiles across diseases. Second, BTG2 lacks enzymatic activity and is completely dependent on its interacting proteins. Furthermore, BTG2's binding affinity may be impacted by its phosphorylation and methylation, and it might be challenging to highlight the precise sites of differential modification during diseases. Because BTG2 lacks enzymatic activity, it is forced to delegate all functional regulation to its non-coding regions. The complementarity of these two aspects yields a fine-tuned context dependency. Additionally, despite its primary localization in the nucleus, BTG2 can undergo nucleocytoplasmic shuttling under specific conditions. Post-translational modifications, such as phosphorylation and acetylation, as well as associated proteins, such as PRMT1, may regulate its subcellular distribution. Notably, BTG2 primarily functions as a nuclear transcriptional regulator, where it may regulate mRNA decay upon cytoplasmic translocation. This localization-based functional switch likely represents a mechanism underlying the pleiotropic roles of BTG2 across tissues and pathological contexts. The biological consequences of BTG2 should therefore be interpreted as a context-dependent functional outcome (loss-of-function state) rather than as a direct reflection of its genomic sequence. No naturally occurring damaging BTG2 variants have been identified in human non-cancerous conditions. However, the knockout model demonstrated the importance of wild-type BTG2 for typical renal development and blood pressure regulation, and its function is strongly modulated by the developmental stage, cell type and sex. Therefore, the loss-of-function mutation is vital to clarify these context-dependent mechanisms, showing that the protective effects of BTG2 are not uniform. Instead, they vary based on the biological environment of BTG2. These findings provide a theoretical framework for understanding the impact of dysregulated wild-type BTG2 expression on disease susceptibility, rather than structural mutation. Importantly, this seeming duality should not be regarded as a contradiction that weakens the relevance of BTG2; rather, it clarifies a profound principle of BTG2 biology. BTG2 dysregulation maintains its relevance for biomarker development and therapeutic investigation in most non-tumor disorders because it is functionally interpretable and directionally consistent. Determining the prevalent pattern of BTG2 dysregulation within a particular microenvironmental and temporal context is still crucial for precision medicine, even in circumstances with bidirectional effects. More generally, the potential that BTG2 exhibits dual-threshold or U-shaped functional activity implies that it may serve as a dose-sensitive homeostatic rheostat, with positive or negative outcomes arising when expression deviates from an optimal range. Beyond this context dependence, this review promotes a more comprehensive conceptualization of BTG2 as a molecular hub located at the interface of multiple pathological systems. The BTG2-centered neuro-immune-epigenetic axis is a particularly compelling framework. Through the BTK-SETD2-H3K36me3-Cx3cr1 cascade, chronic cardiac nociceptive signaling activates inflammatory monocytes in AS. By contrast, VHL-dependent regulation of BTG2 stability modulates endothelial inflammatory responsiveness ( 143 - 145 ). Downstream of p38alpha signaling, BTG2 is a marker of microglial homeostasis in MS, and its decrease facilitates the change from a homeostatic to a disease-associated inflammatory state ( 49 ). By contrast, BTG2 upregulation during the transformation from homeostatic microglia to phagocytic DAM1 states is associated with attenuated amyloid pathology in AD ( 42 ). Taken together, BTG2 is not merely an immune activation marker but also a regulatory node that facilitates the functional coupling of neural cues, immune-state transitions and epigenetic remodeling. Therefore, BTG2 may help determine whether neuroimmune responses continue to be adaptive or shift toward chronic pathology. The metabolic-epigenetic-fibrosis network is a second conceptual axis that emerged from this review. BTG2 appears to play a similar central role in this network. In OSF, arecoline-driven metabolic reprogramming induces YY1 lactylation at K183, which enhances PU.1 activity, promotes BTG2 upregulation, and drives fibroblast senescence and collagen deposition. This pathway serves as a striking example of how metabolic disruption can be transformed into epigenetic instructions, which are subsequently translated into fibrotic remodeling via BTG2. BTG2 plays a similar integrative role in metabolic disease, where it helps maintain hepatic glucose homeostasis by suppressing gluconeogenic enzymes through the action of histone deacetylase ( 100 , 146 ). Collectively, BTG2 functions as an active mediator through which metabolic and epigenetic disturbances yield long-lasting pathological consequences, rather than merely as a passive responder to metabolic stress. Chronic sterile inflammation, extracellular matrix remodeling and fibrosis, oxidative stress and mitochondrial dysfunction, cellular senescence and senescence-associated secretory phenotype, vascular dysfunction and microcirculatory abnormalities, and shared signaling pathways (TGF-β, NLRP3, Wnt, Hippo and mTOR) are the possible features among fibrotic diseases, neurological disorders and cardiovascular diseases. These commonalities point to a potential vicious cycle model involving 'chronic stress-inflammation-remodeling'. However, further research is warranted to clarify the precise shared characteristics of these diseases and the regulatory roles of BTG2. This study investigated the bidirectional effects of BTG2 on fibrosis, the nervous system and the cardiovascular system. Further research is necessary to determine whether this could be attributed to the comparable pathogenic mechanisms among these diseases. BTG2 expression is frequently associated with disease progression and clinical outcome in the aforementioned conditions, underscoring its growing relevance as a mechanistic determinant and a translationally meaningful biomarker. The function of BTG2 in maintaining immune and tissue homeostasis is a recurrent theme that unites these disease states. By controlling mRNA deadenylation via the CCR4-NOT complex, BTG2 maintains T-cell quiescence, thereby reducing aberrant immune activation and preventing loss of self-tolerance ( 147 ). Through myeloid cell-specific mechanisms, BTG2 inhibits unwarranted inflammatory signaling in RA ( 90 ), whereas its deficiency in IBD compromises epithelial resilience, increases susceptibility to injury and impairs mucosal healing ( 91 ). Its immunological relevance is further increased by its role in regulatory T-cell biology. Collectively, these findings position BTG2 as a protector of homeostatic balance, whose dysregulation may contribute to inflammatory amplification, poor resolution and tissue recovery failure. This homeostatic function may represent the shared denominator underlying the seemingly heterogeneous role of BTG2 across organ systems. The growing relevance of BTG2 is equally notable from a translational viewpoint. Multiple studies support its use as a diagnostic or prognostic biomarker across diseases. However, several concerns (including its strong context-dependent and bidirectional effects, as well as the absence of standardized detection protocols) must temper enthusiasm for its clinical translation. Furthermore, BTG2 expression should be interpreted consistently across diseases owing to its strong context dependence. This concept has major ramifications for treatment timing, dose calibration and patient stratification. BTG2 levels have important guiding value from a therapeutic perspective. For instance, high BTG2 expression has been significantly associated with histological remission in IBD. Thus, monitoring BTG2 expression after treatment may indicate mucosal healing. In DKD, reduced BTG2 expression correlates with proteinuria, and stratifying patients based on BTG2 levels may facilitate early intervention to delay DKD progression. BTG2 is markedly downregulated in OSA and its future integration with indicators, such as BTG3, may facilitate molecular subtyping. The dynamic evaluation of disease status and the accurate prediction of complication risk are the main rationale for BTG2-based stratification analyses. To evaluate and standardize its therapeutic applicability, more clinical investigations are required because existing research is still in the exploratory stage. Thus, disease-specific, ideally cell-type-aware, interpretive frameworks are warranted for any therapeutically relevant application. Although intrinsically complicated, BTG2's therapeutic implications are equally promising. Preclinical evidence indicates that BTG2 can be modulated through multiple modalities, including miRNA-based approaches, such as miR-21 ( 148 ), miR-25-3p, miR-29a-3p, miR-322-5p and miR-409-3p. Targeting BTG2-related pathways using physiologically adaptable methods is further demonstrated by exosome-mediated delivery systems, such as IFN-gamma-primed exosomes derived from mesenchymal stromal cells in myocardial infarction models. In parallel, BTG2-associated signaling systems in cardiotoxicity and renal fibrosis appear to be influenced by clinically proven drugs, such as SGLT2i and traditional Chinese medicine formulations ( 33 , 68 ). Therefore, BTG2-centered therapies may be achievable through both direct and indirect mechanisms. However, indiscriminate activation or suppression may pose a risk because BTG2 functions in a context-sensitive and possibly dose-dependent manner. Therefore, rather than relying on universal assumptions of benefit, therapeutic research must shift toward cell-selective, temporally controlled and pathway-informed methods. Despite the advancements synthesized in this review, there are several limitations. First, while rigorous validation in human tissues and prospective clinical research is still limited, a substantial proportion of evidence stems from bioinformatic analysis, cell culture and animal models. Second, the mechanism of action of BTG2 in certain disease domains remains incompletely understood. Third, BTG2's intrinsically disordered C-terminus presents a major obstacle to structural characterization and logical drug discovery, even though it is probably essential to the protein's ability to interact with many binding partners and coordinate several pathways. Thus, the field is still in its early stages of mechanistic maturation, despite the growing conceptual and translational relevance of BTG2. Likewise, the most crucial priorities for further research are determined by these limitations. To advance the science, a quantitative, spatiotemporally resolved understanding of BTG2 biology must replace static and binary models. The BTG2 interactome should be systematically mapped across cell states, tissues and disease situations using advanced proteomics and single-cell multi-omics, while clarifying the upstream regulatory circuits and post-translational modifications that regulate its stability and signaling capacity. Dissecting the stage-dependent roles of BTG2 during disease progression will require conditional and inducible genetic systems with cell-type specificity and temporal control. Furthermore, the identification of expression thresholds that differentiate between adaptive and pathogenic BTG2 activity, the delineation of downstream pathway outputs across expression states and the development of dynamic monitoring strategies that record BTG2 trajectories rather than depending solely on single-timepoint measurements will all be crucial. Large-scale, multicenter validation of BTG2-based biomarker panels is warranted to support clinical implementation. Furthermore, future research should entail combination strategies that target BTG2 along with its upstream regulators or downstream effectors for optimizing therapeutic efficacy while minimizing toxicity. In conclusion, BTG2 has conceptually evolved from a traditional antiproliferative factor into a systems-level regulator of stress adaptation, immune homeostasis and cell-fate determination across non-tumor diseases. Its functions within the neuro-immune-epigenetic axis and the metabolic-epigenetic-fibrosis network underscore its importance as an integrative node in multisystem pathology. Despite substantial mechanistic and translational challenges, existing evidence strongly positions BTG2 as a biologically and clinically important molecule. To comprehensively clarify its potential as a biomarker and a treatment target in refractory non-tumor diseases, a profound understanding of its context-dependent, dose-sensitive and temporally dynamic roles is warranted.