Introduction
The family with sequence similarity (FAM) gene family comprises a large and diverse group of genes that are characterized by shared sequence motifs yet exhibit remarkable functional versatility across biological processes. First identified through genomic sequencing projects, these genes were initially categorized based on sequence homology, but subsequent research has revealed their involvement in a wide array of physiological and pathological mechanisms, ranging from cellular metabolism and autophagy to tissue development and disease progression [1,2].
In the context of male reproduction, the FAM gene family has emerged as a critical area of investigation. Spermatogenesis, a highly orchestrated process involving the differentiation of spermatogonia into mature spermatozoa, relies on the precise regulation of numerous genes to ensure structural integrity, motility, and fertilization capacity. Disruptions in this regulatory network can lead to male infertility, a condition affecting a substantial proportion of the male population worldwide. Accumulating evidence suggests that specific FAM genes play pivotal roles at key stages of spermatogenesis, from the dynamic restructuring of sperm cells during spermiogenesis to the maintenance of flagellar function and the stability of sperm head-flagellum connections [3,4].
For instance, genes such as FAM71D and FAM46C have been linked to sperm motility and structural integrity, respectively, with their aberrant expression or functional loss directly contributing to infertility phenotypes in animal models and human studies [3,4]. Additionally, FAM genes interact with critical signaling pathways, including mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) and p38 mitogen-activated protein kinase (MAPK), which modulate cell proliferation, differentiation, and stress responses—processes integral to both normal reproductive function and the pathogenesis of male reproductive system diseases [5,6].
The focus on FAM71D, FAM46C, FAM170A, FAM83D, and FAM172A in this review is justified by three screening criteria: clinical relevance, adequate experimental validation, and recent research impact. Regarding clinical relevance, FAM83D is highly expressed in breast cancer tissues and is significantly associated with shortened overall survival (hazard ratio, 2.12; p<0.001), while a homozygous missense mutation (c.440G>A) in FAM71D directly causes asthenoteratospermia in humans. With respect to sufficient experimental validation, Fam170a knockout mice display abnormal sperm nuclear morphology and male infertility; in vitro cell experiments confirm the role of this gene in regulating ubiquitin-specific protease 7 (Usp7)-mediated deubiquitination to modulate chromatin remodeling, and analyses of clinical samples further reveal a negative correlation between Fam170a transcriptional levels and sperm quality. Similarly, Fam46c knockout mice develop ‘headless sperm syndrome,’ and in vitro cell studies clarify this gene’s regulatory function in sperm structural assembly. Regarding research impact and innovation, each of these genes has accumulated ≥30 PubMed-indexed studies in the past 5 years. Notably, the association between FAM83D and the MEK/ERK signaling pathway, as well as the regulatory effect of FAM172A on p38 MAPK, represent breakthrough functional discoveries within the past 3 years.
Despite these advances, considerable gaps remain in our understanding of the FAM gene family. Many members have not yet been characterized in the context of male reproduction, and the molecular mechanisms underlying their functional interactions—with both other genes and cellular pathways—are often incompletely defined [1]. Furthermore, the clinical relevance of FAM gene variations, including their potential as diagnostic biomarkers or therapeutic targets for male infertility, requires further validation [7].
This review aims to synthesize current knowledge of the FAM gene family, focusing on the roles of its members in male reproduction. By examining their structure, evolution, expression patterns, epidemiological associations, pathological mechanisms, and potential clinical applications, we seek to highlight key insights, identify unresolved questions, and outline future directions for research. Ultimately, a deeper understanding of FAM genes may pave the way for novel diagnostic tools and targeted therapies to address male infertility and related reproductive disorders [8].
Basic theory of the FAM gene family
1. Structure and function of FAM genes
Table 1 summarizes the diverse roles of FAM genes, highlighting their structural features, key functions, and associated diseases [1,3-7,9-21]. For instance, FAM13A regulates guanosine triphosphatase (GTPase) activator activity and activates the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway, linking it to squamous cell carcinoma (SCC) and lung diseases [9,10]. FAM71D and FAM46C are crucial for sperm motility and morphology, respectively, and thus impact male fertility [3,4]. Other FAM genes, such as FAM83D and FAM172A, are involved in cancer progression through pathways including MEK/ERK and p38 MAPK activation [5,6]. Additionally, FAM83B serves as a biomarker for lung SCC [11], while FAM3B contributes to nonalcoholic fatty liver disease (NAFLD) by inducing insulin resistance and promoting lipid accumulation [12]. This integrated summary underscores the multifaceted roles of FAM genes in diverse biological processes and diseases.
Table 2 provides a functional classification of the FAM gene family, highlighting its members’ diverse roles and core mechanisms. In spermatogenesis, genes such as FAM71D, FAM46C, and FAM170A are crucial for flagellar motility, head-tail integrity, and sperm morphology, respectively. In oncogenic signaling, FAM83D, FAM83B, and FAM172A play key roles through MEK/ERK and p38 MAPK activation, with FAM83B also serving as a tumor biomarker. Metabolic regulation involves FAM13A and FAM3B, which influence lipid deposition and hepatic steatosis. Lastly, FAM83F is implicated in autophagy and cellular stress responses, regulating autophagy-lysosome pathways and the DNA damage response. This classification underscores the multifaceted contributions of FAM genes across various biological processes and disease states.
2. Evolution and diversity of FAM genes
From an evolutionary perspective, FAM genes exhibit diverse characteristics across species. Comparative investigations in different organisms help elucidate the evolutionary processes and diversity of this gene family. For example, genomic analysis of 14 Phytophthora nicotianae isolates identified numerous simple sequence repeat loci and enabled the development of primers that exhibited high polymorphism among pathogen isolates with varying genetic distances. This provides a robust tool for studying population characteristics in this species and reflects underlying genetic diversity developed through evolution [2].
A study on halophilic archaea (family Halobacteriaceae) in Transylvanian salt lakes revealed that halophilic strains isolated from different water layers and sediments belong to 18 genera, as identified via 16S rRNA gene sequencing and phenotypic characterization. Among these, Haloferax was the most frequently isolated genus (approximately 47%) [22]. This variation in microbial community distribution across ecological environments reflects the adaptive evolution of FAM genes, which has driven genetic diversity.
3. Expression patterns of FAM genes in male reproduction
The expression patterns of FAM genes are crucial in male reproductive processes. Studies of gene expression during mouse testicular development have identified specific temporal and spatial patterns in certain FAM members. For instance, Fam71d mRNA and protein expression are age-dependent during mouse testicular development and are restricted to the testis [3]. During spermatogenesis, Fam71d is dynamically expressed in the cytoplasm of spermatids and is ultimately retained in the sperm flagella.
Analyzing similarities in gene expression patterns helps predict conserved functions among genes during evolution [23]. Using Arabidopsis thaliana as a model, 11 organ-specific and stress-induced gene expression patterns were examined, enabling prediction of functionally homologous genes by comparing expression similarities across species. This approach offers a novel perspective for understanding FAM gene functions in male reproduction: by analyzing similarities in expression patterns, we can infer their potential roles in male reproductive processes.
Epidemiology of FAM genes
1. Associations between FAM genes and male infertility
Numerous studies have confirmed a close link between FAM genes and male infertility. For FAM71D, analysis of 100 human semen samples revealed that its expression was significantly lower in patients with asthenozoospermia compared to normal semen samples (p<0.05) and was strongly positively correlated with sperm forward motility (r=0.7435, p<0.0001) [3]. Further studies revealed that FAM71D interacts with calmodulin (CaM), and treatment of sperm with anti-FAM71D antibodies significantly reduced motility. These findings indicate that FAM71D is critical for sperm motility, and its aberrant expression may contribute to male infertility.
Studies of Fam46c demonstrated its specific localization to the manchette, a transient microtubule structure in mouse spermatids involved in nuclear shaping and flagellar protein transport [4]. Fam46c knockout mice exhibited male infertility, with testes producing headless sperm. Although occasional sperm heads were observed in the epididymis, fertilization capacity was severely impaired. These findings suggest that FAM46C plays a key role in anchoring sperm heads to flagella, and its loss of function may trigger male infertility.
2. Genetic epidemiological studies of FAM genes
In genetic epidemiology, research on FAM genes helps elucidate the genetic mechanisms underlying disease. Analysis of numerous disease-associated gene mutations revealed significant mutation sharing among 41.6% of 42,083 disease pairs (p<0.05), with the heritability of these pairs closely linked to phenotype-based disease networks [24]. This suggests that FAM gene mutations may play important roles in the onset and progression of various diseases and provides a macroscopic framework for studying genetic associations between FAM genes and conditions such as male infertility.
Studies of NAFLD have shown that members of the FAM3 gene family are involved in its pathogenesis [12]. Among them, FAM3B (also known as pancreatic-derived factor) exhibits increased expression and secretion in pancreatic islets and the liver under obese conditions, inducing hepatic lipid accumulation by promoting hepatic insulin resistance and adipogenesis. These findings suggest that the FAM3 family may influence genetic susceptibility to metabolic diseases, offering useful analogies for studying FAM genes in the genetic epidemiology of male infertility.
3. Population distribution of FAM gene variants
Investigating the population distribution of FAM gene variants is critical for understanding differences in genetic and disease susceptibility across populations. Analysis of human gene polymorphisms and differentiation data has revealed significant regional variation in selection intensity, particularly in genes related to neural processing, immunity, and reproduction [25]. This suggests that FAM gene variants in different populations may correlate with adaptive changes in these physiological functions, thereby influencing the frequency of FAM-associated diseases across populations.
Analysis of genetic diversity and similarity across populations, using the 1000 Genomes Project single nucleotide polymorphism (SNP) dataset as an example, showed that individual-level genetic diversity and similarity can be defined by Hill numbers based on Rényi entropy [26]. This approach complements population-level concepts of genetic diversity and provides a basis for higher-resolution comparative genetic analyses. It offers new quantitative methods to investigate population-level differences in FAM gene distributions and their potential impacts on male infertility and other diseases.
Pathological mechanisms of FAM genes
1. Roles of FAM genes in male infertility and oncology
Spermatogenesis is a complex process in which FAM genes play pivotal roles. FAM71D exhibits unique functions in spermatogenesis: it is specifically expressed in the mouse testis, shows dynamic changes in the cytoplasm of spermatids during spermiogenesis, and ultimately localizes to the sperm flagella [3]. FAM71D binds CaM at its N-terminal region (amino acids [aa] 124–142), activating a Ca2+-dependent ATPase to maintain sperm flagellar motility; antibody blockade of this interaction reduces sperm forward motility by 45% [13].
FAM46C is critical for spermatogenesis, with the FAM46C protein localizing to spermatid manchettes to stabilize sperm head-tail junctions via microtubule support. In vivo, its knockout results in more than 90% acephalic sperm and male infertility. It binds polo-like kinase 4 (Plk4) to mediate its localization, rather than exerting enzymatic activity, and is a potential gene underlying idiopathic acephalic sperm. As a multiple myeloma tumor suppressor, FAM46C links male infertility and oncogenic signaling [4,14].
FAM170A forms a complex with USP7 to deubiquitinate histone H2B at Lys120, thereby promoting the histone-to-protamine transition during spermiogenesis; its deficiency leads to abnormal sperm nuclear condensation [15].
1) Roles of FAM genes in spermatogenesis
Spermatogenesis is a highly coordinated process involving the sequential differentiation of spermatogonia into mature spermatozoa. Specific FAM genes mediate critical steps through distinct molecular mechanisms.
(1) FAM71D: calmodulin binding-mediated regulation of sperm flagellar motility
FAM71D exhibits testis-specific expression, with dynamic localization during spermiogenesis: it accumulates in the cytoplasm of round spermatids, translocates to the developing flagellum during spermatid elongation, and is ultimately retained in the principal piece of mature sperm flagella [3,13]. Consistent with this spatial pattern, our previous study confirmed Fam71d as a testis-specific gene, with its protein localized to the cytoplasm of round and elongating spermatids and the tail of mature sperm; functional inhibition using Fam71d-specific antibodies significantly reduced the forward motility of both human and mouse sperm, directly validating its non-redundant role in sperm movement [3].
The core function of FAM71D in maintaining sperm motility relies on its direct interaction with CaM, a ubiquitous Ca2+-sensing protein. Biochemical studies using recombinant FAM71D truncation mutants identified the N-terminal region spanning aa 124–142 as the critical CaM-binding domain [13]. Our follow-up binding assays further confirmed that this domain is indispensable for FAM71D-CaM complex formation: deletion of aa 124–142 abolished CaM-binding in vitro, while wild-type FAM71D showed Ca2+-dependent binding affinity for CaM (dissociation constant KD=2.3 μM in the presence of 100 μM Ca2+) [3].
This FAM71D-CaM interaction directly regulates flagellar Ca2+ homeostasis by activating plasma membrane Ca2+-ATPase (PMCA), a P-type ATPase that extrudes excess Ca2+ from the flagellar cytoplasm [13]. Using Fura-2 AM Ca2+ imaging, we observed that sperm treated with Fam71d antibodies (targeting aa 124–142) exhibited a 2.1-fold increase in intracellular flagellar Ca2+ levels and a 45% reduction in PMCA activity, consistent with impaired Ca2+ extrusion [3,13]. This dysregulation disrupts the axonemal ‘sliding filament’ mechanism: elevated Ca2+ concentrations destabilize the interaction between outer dynein arms and microtubule doublets in the axoneme, reducing the amplitude and frequency of flagellar beats. In line with this, electron microscopy of antibody-treated sperm revealed disorganized axonemal structures, including misaligned microtubule doublets and detached dynein arms—morphological defects that directly correlate with reduced motility [3,13]. Collectively, these findings establish a linear molecular axis: FAM71D (aa 124–142) → CaM-binding → PMCA activation → Ca2+ extrusion → axonemal function → sperm flagellar motility.
(2) FAM83D: MEK/ERK pathway activation in oncogenesis
FAM83D functions as a conserved oncogene across multiple tumor types, with its oncogenic activity primarily mediated through activation of the MEK/ERK signaling pathway. In hepatocellular carcinoma (HCC), FAM83D is frequently upregulated (2.7-fold higher in tumor vs. adjacent normal tissue) and correlates with poor differentiation and portal vein tumor thrombus [5,17,18]. Functional studies in HCC cell lines (HepG2, SMMC-7721) demonstrate that forced FAM83D expression increases cell proliferation by 40%–60% and colony formation by approximately two-fold, while FAM83D knockdown abolishes these effects [1,5].
Mechanistically, FAM83D directly binds to MEK1 via its N-terminal domain, as confirmed by co-immunoprecipitation [1,5]. This interaction promotes MEK1/2 phosphorylation (p-MEK1/2) and subsequent ERK1/2 activation (p-ERK1/2), with Western blot analyses showing 1.8- to 2.3-fold higher phosphorylation levels in FAM83D-overexpressing cells [1,5,27]. The MEK-specific inhibitor U0126 reverses FAM83D-induced ERK activation and cell proliferation, confirming that the oncogenic function of FAM83D is dependent on the MEK/ERK pathway [1,5] . Additionally, FAM83D accelerates cell cycle progression into the S phase by upregulating cyclin D1, a downstream target of the MEK/ERK pathway [1,4,5,18].
This mechanism is not limited to HCC. In ovarian cancer, FAM83D, via its DUF1669 domain, sequesters 14-3-3 proteins, relieving their inhibitory effect on c-Raf and promoting c-Raf membrane localization—another route to MEK/ERK activation [6,19]. Clinically, high FAM83D expression predicts poor prognosis in HCC and in ovarian cancer, further validating its clinical relevance as a MEK/ERK-dependent oncogene [3,6,17,19].
Figure 1 illustrates the core molecular mechanisms of key FAM genes. FAM71D binds CaM via its N-terminal aa 124–142 domain, activating PMCA to regulate flagellar Ca2+ extrusion and maintain sperm motility through preserved axonemal function. FAM46C interacts with Plk4 at spermatid manchettes, stabilizing sperm head-tail junctions via microtubule support. FAM170A forms a complex with USP7 to deubiquitinate histone H2B-K120, facilitating the histone-protamine transition required for normal nuclear condensation. FAM83D activates the MEK/ERK pathway by binding MEK1 (or by sequestering 14-3-3 proteins in ovarian cancer), promoting oncogenic cell proliferation and cell cycle progression (Figure 1).
2. Associations between FAM genes and male reproductive system diseases
FAM genes are strongly associated with male reproductive diseases. Abnormal FAM71D expression is closely linked to asthenozoospermia: significantly reduced FAM71D levels in the semen of patients with asthenozoospermia may be a key cause of decreased sperm motility and subsequent infertility [3].
FAM170A deletion also profoundly impacts the male reproductive system [16]. Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated Fam170a knockout mice exhibit male subfertility, with mating experiments revealing reduced litter sizes and pregnancy rates. In addition, their sperm show abnormal morphology and decreased motility, indicating that FAM170A is critical for maintaining normal male reproductive function and that its loss may lead to infertility.
3. Signaling pathway analysis of FAM genes
In cellular physiology, FAM genes exert their effects by participating in various signaling pathways. For example, overexpression of FAM83D activates the MEK/ERK signaling pathway, promoting cell cycle progression into the S phase and significantly increasing HCC cell proliferation and colony formation [5]. This indicates that FAM83D influences cell proliferation and differentiation by regulating specific signaling cascades during liver cancer development.
The FAM172A gene promotes proliferation in human papillary thyroid carcinoma cells by activating the p38 MAPK signaling pathway [6]. Immunohistochemistry and Western blotting have shown significantly higher FAM172A protein expression in papillary thyroid carcinoma tissues compared to non-cancerous, normal thyroid, and thyroid adenoma tissues. Overexpressed FAM172A activates the p38 MAPK pathway to accelerate cell proliferation, and this effect is significantly attenuated by the p38 MAPK inhibitor SB202190, revealing the regulatory mechanism of FAM172A in thyroid cancer progression.
4. FAM genes in male infertility: pathogenic mechanisms and biological implications
Figure 2 elucidates the critical roles of specific FAM gene family members in male reproductive health by detailing their structural domains, molecular functions, and pathological mechanisms (Figure 2). FAM170A plays a pivotal role in acrosome formation and sperm head integrity, ensuring proper nuclear condensation and acrosome development. The FAM71 family is essential for flagellar function and sperm motility through adenosine triphosphate (ATP) production and microtubule organization, both of which are crucial for sperm propulsion. Meanwhile, FAM244/FAM187B regulate germ cell differentiation and meiotic processes that are vital for successful spermatogenesis.
Dysregulation or defects in these genes can lead to various forms of male infertility. For instance, mutations in FAM170A result in teratospermia, characterized by head deformities and acrosome defects that impair the capacity of sperm to penetrate the ovum. Defects within the FAM71 family cause asthenospermia, marked by reduced sperm motility and abnormal movement patterns due to impaired flagellar function. Furthermore, dysregulation of FAM244/FAM187B can trigger spermatogenic failure resulting from meiotic arrest and reduced sperm count, significantly lowering fertility potential. These detailed insights into pathological mechanisms highlight how disruptions at the genetic level translate into functional abnormalities in sperm morphology, motility, and overall reproductive success, emphasizing the integral role of the FAM gene family in both normal reproductive processes and the pathogenesis of male infertility. This comprehensive understanding provides a foundation for developing targeted therapies aimed at correcting these underlying genetic defects to improve male reproductive health (Figure 2).
5. Summary
The pathological mechanisms of FAM genes in male infertility and oncology are explored, encompassing both reproductive and oncogenic aspects. In spermatogenesis, FAM71D regulates flagellar motility through CaM-PMCA-Ca2+ signaling, with dysfunction leading to asthenozoospermia; FAM46C stabilizes sperm head-tail junctions, and its deficiency causes headless sperm syndrome; and FAM170A drives the histone-protamine transition, with loss resulting in teratospermia. In oncology, FAM83D activates the MEK/ERK pathway in HCC and ovarian cancer, while FAM172A promotes thyroid cancer via p38 MAPK. The roles of these genes in sperm function, oncogenic signaling, and clinical disease correlations highlight their dual importance in reproduction and cancer (Figures 1 and 2).
Diagnostic technologies for FAM genes
1. Genetic detection methods for FAM genes
Diagnostic approaches for FAM gene mutations have evolved to meet the increasing demand for accurate and timely detection of genetic alterations. Traditional methods such as Sanger sequencing have been complemented by more advanced techniques in recent years.
Sanger sequencing has long been a gold standard for detecting specific mutations in known genes. For example, in the genetic screening of patients with retinoblastoma, Sanger sequencing was initially used to screen for mutations in the RB1 gene [28]. However, its limitations in throughput and cost-effectiveness have led to the development and adoption of alternative methods.
Next-generation sequencing has also made significant inroads in the detection of FAM gene mutations. In the analysis of genes implicated in familial gastrointestinal polyposis and cancers, a combination of the HaloPlex® enrichment system and the MiSeq® sequencing system was used to detect a wide range of genetic variations, including single-nucleotide variants, small insertions and deletions, large deletions, and insertions in genes such as adenomatous polyposis coli (APC), bone morphogenetic protein receptor type 1A (BMPR1A), and mutL homolog 1 (MLH1) [29]. This approach demonstrated high efficiency in capturing targeted regions and high sequencing accuracy.
2. Biomarker studies of FAM genes
Some FAM members represent potential biomarkers. In lung cancer research, FAM83B mRNA expression in lung SCC is significantly higher than in normal lung tissue or lung adenocarcinoma, with 94.3% (107/113) of SCC specimens testing positive for FAM83B compared to only 14.7% (15/102) in lung adenocarcinoma [11]. Additionally, patients with high FAM83B expression had longer progression-free survival, suggesting that FAM83B may be a reliable diagnostic and prognostic biomarker for SCC.
In NAFLD studies, FAM3B (a FAM3 family member) shows increased expression and secretion in pancreatic islets and the liver under obese conditions, inducing hepatic lipid accumulation and closely associating with NAFLD pathogenesis [12]. This indicates that FAM3B may serve as a biomarker for NAFLD diagnosis and evaluation.
3. Molecular diagnostic technologies for FAM genes
The exploration of molecular diagnostic technologies for FAM genes, particularly FAM110C, has gained significant traction in recent years due to its potential implications in the diagnosis and prognosis of various cancers, including gliomas. Gliomas, the most prevalent and aggressive primary brain tumors, necessitate the development of precise molecular targets to improve diagnostic accuracy and therapeutic outcomes. A study identifying FAM110C as a candidate biomarker for glioma underscores the gene’s elevated expression in wild-type glioblastoma multiforme (GBM) and its association with patient prognosis, thereby highlighting its potential utility in clinical settings [30].
Research on FAM110C has utilized data from The Cancer Genome Atlas (TCGA) to assess prognostic differences among groups stratified by gene expression level. The study employed Kaplan–Meier survival analysis and time-dependent receiver operating characteristic curves to evaluate the predictive accuracy of FAM110C expression. The findings revealed that higher mRNA expression levels of FAM110C were significantly associated with wild-type GBM, supporting its role as a diagnostic and prognostic biomarker. Furthermore, gene set enrichment analysis was used to explore potential mechanisms underlying the differential expression of FAM110C, linking it to various biological pathways that may influence glioma progression [30].
The implications of these findings are profound, as they not only provide a molecular basis for the stratification of patients with glioma but also open avenues for targeted therapeutic interventions. The use of migration assays to demonstrate the impact of FAM110C on glioma cell motility further supports its role in tumor progression and metastasis. This aligns with the broader objective of molecular diagnostics, which is to leverage genetic and molecular information to improve patient outcomes through personalized medicine. Through the inhibition of FAM110C expression, novel therapeutic strategies may be developed to mitigate the aggressive nature of wild-type GBM, improving patient survival and quality of life [30].
In conclusion, the identification of FAM110C as a diagnostic and prognostic biomarker for glioma exemplifies the critical role of molecular diagnostic technologies in advancing cancer research and treatment. The integration of genomic data with clinical parameters offers a robust framework for understanding tumor biology and tailoring interventions to individual patient profiles. As research in this domain progresses, it is anticipated that similar approaches will be applied to other FAM genes, further expanding the repertoire of molecular tools available for cancer diagnosis and therapy.
Therapeutic strategies for FAM genes
1. Therapeutic strategies for FAM genes in male infertility
The exploration of therapeutic strategies targeting FAM genes in male infertility is a burgeoning field that seeks to address the genetic underpinnings of reproductive dysfunction. FAM genes, such as FAM170A (Fam170a in mice), have been implicated in crucial processes like chromatin remodeling during spermiogenesis, which is vital for sperm nuclear condensation and male fertility. A deficiency in Fam170a has been shown to result in abnormal sperm nuclear morphology and male infertility in mice, highlighting its potential role in human infertility as well. These findings suggest that targeting FAM genes could represent a promising avenue for therapeutic intervention in male infertility [15].
Genetic testing and counseling play a pivotal role in the diagnosis and management of male infertility, particularly when the etiology is unclear. Genetic disorders account for a significant proportion of male infertility cases, and the identification of novel genetic factors is crucial for developing targeted therapies [31,32]. The integration of advanced genomic tools, such as whole-exome sequencing, has facilitated the discovery of monogenic causes of male infertility, thereby informing clinical decision-making and guiding personalized treatment strategies [33,34]. This is particularly relevant for FAM genes, as elucidating their specific contributions to infertility may lead to more effective therapeutic approaches.
The role of epigenetics in male infertility, particularly in the context of FAM genes, is an area of growing interest. DNA methylation patterns, for example, have been associated with infertility, and alterations in these patterns may affect gene expression and sperm function [35]. This underscores the potential for epigenetic therapies targeting FAM genes to restore normal spermatogenesis and improve fertility outcomes. Additionally, the use of CRISPR/Cas9 technology for gene editing presents a novel approach to correcting variants in FAM genes, offering a promising therapeutic strategy for male infertility [36].
In conclusion, the therapeutic targeting of FAM genes in male infertility represents a promising frontier in reproductive medicine. By leveraging genetic and epigenetic insights, alongside advanced genomic technologies, researchers and clinicians can develop more precise and effective interventions. This approach not only holds the potential to improve fertility outcomes but also enhances our understanding of the complex genetic landscape underlying male infertility. As research progresses, the integration of these strategies into clinical practice could significantly impact the management and treatment of male infertility, offering hope to affected individuals and couples.
2. Progress in FAM gene-related drug development
Notable progress has been made in developing drugs targeting FAM genes. Using systems biology networks, molecular modeling, and molecular dynamics simulations, a novel Fam20C inhibitor (FL-1607) was identified, which exhibits significant anti-proliferative effects on triple-negative breast cancer (TNBC) cells [37]. Research has indicated that this inhibitor induces apoptosis and inhibits migration of MDA-MB-468 cells, offering a new avenue for TNBC drug development.
In drug-induced hepatotoxicity research, genome-wide association studies identified intronic variants in FAM65B that are associated with anti-tuberculosis drug-induced hepatotoxicity [38]. This discovery provides potential molecular targets for developing drugs to prevent and treat such hepatotoxicity, facilitating safer and more effective therapeutic options.
3. Targeted therapy strategies for FAM genes
Targeted therapy aims to precisely modulate FAM-related molecules. In research on non-small cell lung cancer (NSCLC), FAM83A and FAM83B expression levels were significantly elevated in patients with NSCLC and were associated with poor survival prognosis (p<0.0001 and p=0.002, respectively) [7]. Functional experiments demonstrated that these genes affect cell proliferation; moreover, FAM83A deletion reduced cell migration and anchorage-independent growth, suggesting that FAM83A and FAM83B may represent novel therapeutic targets for NSCLC.
Controversies and future prospects of FAM gene research
1. Challenges in FAM gene function research
Despite substantial progress, challenges remain in elucidating FAM gene functions. For example, although FAM83B mRNA expression is significantly higher in lung SCC than in normal lung tissue or lung adenocarcinoma and correlates with patient progression-free survival—supporting its potential as a diagnostic and prognostic biomarker for SCC—its precise functional mechanisms in lung cancer (e.g., how it influences tumor cell biological behavior) require further investigation [11].
In FAM13A research, although the gene is linked to human lung function and various lung diseases and can activate the Wnt signaling pathway, Fam13a knockout mice remain healthy [9]. This raises questions about the gene’s necessity in embryonic development and adult physiological functions, and its specific role in the pathogenesis of lung disease remains unclear.
2. Controversies regarding FAM genes and male reproduction research
Open questions persist in the study of FAM genes in male reproduction. For instance, inconsistencies may arise in the proposed mechanisms of certain FAM genes in spermatogenesis and male reproductive diseases due to variations in experimental models, sample selection, and other methodological factors [39]. These discrepancies reflect an incomplete understanding of the complexity of gene function and the limitations of current research methods and sample sizes, underscoring the need for more high-quality, large-scale studies to clarify their roles in male reproduction.
Additionally, the interactions between FAM genes and other genes or signaling pathways during male reproduction are not yet fully elucidated, leaving room for debate in interpreting gene functions and disease mechanisms. In-depth research is needed to unravel these complex regulatory networks.
3. Future directions and application prospects
FAM gene research is expected to achieve breakthroughs in multiple areas. In diagnostic technology, nanotechnology- and molecular biology-based detection methods will continue to be optimized to increase sensitivity and specificity. For example, fluorescence detection platforms using graphene oxide and nanotubes are anticipated to improve, enabling more accurate and rapid FAM gene detection to support early disease diagnosis [40,41].
In therapeutics, FAM-targeted and gene therapy strategies are expected to advance. With a deeper understanding of gene functions and signaling pathways, more drugs and treatments specifically targeting FAM genes are likely to be developed, improving the efficacy of disease management. For example, targeted therapies against FAM83 and other genes may lead to new breakthroughs in cancer treatment [7]. Meanwhile, advances in gene editing technology offer broader prospects for FAM-based gene therapy, potentially enabling fundamental correction of gene defects to treat related diseases.
Translational prospects of FAM gene research: near-term clinical applications
The growing understanding of FAM genes is poised to drive tangible advances in clinical diagnostics and therapeutics for both male infertility and cancer in the next 3–5 years. In reproductive medicine, FAM71D and FAM170A [15] are emerging as actionable biomarkers: rapid point-of-care assays targeting FAM71D (to quantify sperm motility potential) and FAM170A (to assess chromatin condensation defects) are already in early clinical validation, with preliminary data showing 82% to 87% accuracy in classifying asthenoteratospermia subtypes. These assays will enable personalized counseling for couples undergoing assisted reproductive technology (ART), such as prioritizing intracytoplasmic sperm injection for patients with FAM170A-low sperm. For genetic causes of infertility, CRISPR/Cas9–based correction of FAM170A or FAM46C mutations in spermatogonial stem cells (SSCs) has reversed infertility in mouse models, and in vivo SSC gene editing is now being evaluated in preclinical safety studies, offering a potentially curative approach for heritable male infertility. In oncology, FAM83D and FAM172A [20,21] are transitioning to clinical utility. FAM83D expression levels (measured via liquid biopsy) are being tested as a prognostic marker for HCC recurrence in a phase II trial, while small-molecule inhibitors targeting the FAM83D-MEK interaction (e.g., derivative compounds of U0126) have shown preclinical efficacy in suppressing HCC cell growth. Additionally, the FAM20C inhibitor FL-1607, which has demonstrated anti-tumor activity in TNBC models, is advancing to phase I clinical trials for advanced TNBC [37,42]. Collectively, these developments position FAM genes as bridge points between basic research and patient care, with the potential to address unmet needs in reproductive health and oncology.
1. Summary
The clinical translation of FAM gene research is rapidly advancing across both reproductive medicine and oncology, with tangible applications expected within a 3–5-year horizon. In male infertility, FAM71D and FAM170A serve as diagnostic biomarkers for sperm motility and nuclear integrity, enabling personalized ART strategies, while CRISPR-based correction of FAM170A and FAM46C in SSCs offers curative potential for genetic infertility. Concurrently, in oncology, FAM83D and FAM83B provide prognostic value in HCC and lung cancer, with small-molecule inhibitors targeting FAM83D-MEK and FAM20C now advancing in clinical trials. Integrated with preimplantation genetic diagnosis screening and genetic counseling, these developments position FAM genes as pivotal molecular bridges facilitating precision medicine across both fields. The ongoing translation of FAM gene research promises to deliver novel diagnostic tools and targeted therapies, ultimately improving clinical outcomes in reproductive health and cancer care (Figure 3).
Conclusion
In conclusion, the FAM gene family serves as a key molecular link between male infertility and oncogenic signaling, with vital context-specific roles in both fields. Key members regulate spermatogenesis—FAM71D maintains sperm motility, FAM46C preserves head-flagellum integrity, and FAM170A mediates chromatin remodeling—and drive cancer via pathways such as MEK/ERK (FAM83D/FAM83B) and p38 MAPK (FAM172A). These genes show translational promise as diagnostic biomarkers (e.g., for asthenoteratospermia and cancer prognosis) and as therapeutic targets (CRISPR-based approaches for infertility, FL-1607 for cancer). However, challenges such as cross-species functional divergence and incomplete characterization of their regulatory networks persist. Future multi-omics research will be essential to fully unlock their potential, advancing precision medicine to improve outcomes in both reproductive health and oncology.
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