SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species.

DNA repair has been hypothesized to be a longevity determinant, but the evidence for it is based largely on accelerated aging phenotypes of DNA repair mutants. Here, using a panel of 18 rodent species with diverse lifespans, we show that more robust DNA double-strand break (DSB) repair, but not nucleotide excision repair (NER), coevolves with longevity. Evolution of NER, unlike DSB, is shaped primarily by sunlight exposure. We further show that the capacity of the SIRT6 protein to promote DSB repair accounts for a major part of the variation in DSB repair efficacy between short- and long-lived species. We dissected the molecular differences between a weak (mouse) and a strong (beaver) SIRT6 protein and identified five amino acid residues that are fully responsible for their differential activities. Our findings demonstrate that DSB repair and SIRT6 have been optimized during the evolution of longevity, which provides new targets for anti-aging interventions.

Spliced X-box binding protein 1 couples the unfolded protein response to hexosamine biosynthetic pathway.

The hexosamine biosynthetic pathway (HBP) generates uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) for glycan synthesis and O-linked GlcNAc (O-GlcNAc) protein modifications. Despite the established role of the HBP in metabolism and multiple diseases, regulation of the HBP remains largely undefined. Here, we show that spliced X-box binding protein 1 (Xbp1s), the most conserved signal transducer of the unfolded protein response (UPR), is a direct transcriptional activator of the HBP. We demonstrate that the UPR triggers HBP activation via Xbp1s-dependent transcription of genes coding for key, rate-limiting enzymes. We further establish that this previously unrecognized UPR-HBP axis is triggered in a variety of stress conditions. Finally, we demonstrate a physiologic role for the UPR-HBP axis by showing that acute stimulation of Xbp1s in heart by ischemia/reperfusion confers robust cardioprotection in part through induction of the HBP. Collectively, these studies reveal that Xbp1s couples the UPR to the HBP to protect cells under stress.

Dendrite intercalation between epidermal cells tunes nociceptor sensitivity to mechanical stimuli in Drosophila larvae.

An animal's skin provides a first point of contact with the sensory environment, including noxious cues that elicit protective behavioral responses. Nociceptive somatosensory neurons densely innervate and intimately interact with epidermal cells to receive these cues, however the mechanisms by which epidermal interactions shape processing of noxious inputs is still poorly understood. Here, we identify a role for dendrite intercalation between epidermal cells in tuning sensitivity of Drosophila larvae to noxious mechanical stimuli. In wild-type larvae, dendrites of nociceptive class IV da neurons intercalate between epidermal cells at apodemes, which function as body wall muscle attachment sites, but not at other sites in the epidermis. From a genetic screen we identified miR-14 as a regulator of dendrite positioning in the epidermis: miR-14 is expressed broadly in the epidermis but not in apodemes, and miR-14 inactivation leads to excessive apical dendrite intercalation between epidermal cells. We found that miR-14 regulates expression and distribution of the epidermal Innexins ogre and Inx2 and that these epidermal gap junction proteins restrict epidermal dendrite intercalation. Finally, we found that altering the extent of epidermal dendrite intercalation had corresponding effects on nociception: increasing epidermal intercalation sensitized larvae to noxious mechanical inputs and increased mechanically evoked calcium responses in nociceptive neurons, whereas reducing epidermal dendrite intercalation had the opposite effects. Altogether, these studies identify epidermal dendrite intercalation as a mechanism for mechanical coupling of nociceptive neurons to the epidermis, with nociceptive sensitivity tuned by the extent of intercalation.

Mechanical stress can regulate temporomandibular joint cavitation via signalling pathways.

The temporomandibular joint (TMJ), composed of temporal fossa, mandibular condyle and a fibrocartilage disc with upper and lower cavities, is the biggest synovial joint and biomechanical hinge of the craniomaxillofacial musculoskeletal system. The initial events that give rise to TMJ cavities across diverse species are not fully understood. Most studies focus on the pivotal role of molecules such as Indian hedgehog (Ihh) and hyaluronic acid (HA) in TMJ cavitation. Although biologists have observed that mechanical stress plays an irreplaceable role in the development of biological tissues and organs, few studies have been concerned with how mechanical stress regulates TMJ cavitation. Based on the evidence from human or other animal embryos today, it is implicated that mechanical stress plays an essential role in TMJ cavitation. In this review, we discuss the relationship between mechanical stress and TMJ cavitation from evo-devo perspectives and review the clinical features and potential pathogenesis of TMJ dysplasia.

Nitrosative stress drives heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with high morbidity and mortality for which there are no evidence-based therapies. Here we report that concomitant metabolic and hypertensive stress in mice-elicited by a combination of high-fat diet and inhibition of constitutive nitric oxide synthase using Nω-nitro-L-arginine methyl ester (L-NAME)-recapitulates the numerous systemic and cardiovascular features of HFpEF in humans. Expression of one of the unfolded protein response effectors, the spliced form of X-box-binding protein 1 (XBP1s), was reduced in the myocardium of our rodent model and in humans with HFpEF. Mechanistically, the decrease in XBP1s resulted from increased activity of inducible nitric oxide synthase (iNOS) and S-nitrosylation of the endonuclease inositol-requiring protein 1α (IRE1α), culminating in defective XBP1 splicing. Pharmacological or genetic suppression of iNOS, or cardiomyocyte-restricted overexpression of XBP1s, each ameliorated the HFpEF phenotype. We report that iNOS-driven dysregulation of the IRE1α-XBP1 pathway is a crucial mechanism of cardiomyocyte dysfunction in HFpEF.

BACH1 deficiency prevents neointima formation and maintains the differentiated phenotype of vascular smooth muscle cells by regulating chromatin accessibility.

The transcription factor BTB and CNC homology 1(BACH1) has been linked to coronary artery disease risk by human genome-wide association studies, but little is known about the role of BACH1 in vascular smooth muscle cell (VSMC) phenotype switching and neointima formation following vascular injury. Therefore, this study aims to explore the role of BACH1 in vascular remodeling and its underlying mechanisms. BACH1 was highly expressed in human atherosclerotic plaques and has high transcriptional factor activity in VSMCs of human atherosclerotic arteries. VSMC-specific loss of Bach1 in mice inhibited the transformation of VSMC from contractile to synthetic phenotype and VSMC proliferation and attenuated the neointimal hyperplasia induced by wire injury. Mechanistically, BACH1 suppressed chromatin accessibility at the promoters of VSMC marker genes via recruiting histone methyltransferase G9a and cofactor YAP and maintaining the H3K9me2 state, thereby repressing VSMC marker genes expression in human aortic smooth muscle cells (HASMCs). BACH1-induced repression of VSMC marker genes was abolished by the silencing of G9a or YAP. Thus, these findings demonstrate a crucial regulatory role of BACH1 in VSMC phenotypic transition and vascular homeostasis and shed light on potential future protective vascular disease intervention via manipulation of BACH1.

Long-distance association of topological boundaries through nuclear condensates.

The eukaryotic genome is partitioned into distinct topological domains separated by boundary elements. Emerging data support the concept that several well-established nuclear compartments are ribonucleoprotein condensates assembled through the physical process of phase separation. Here, based on our demonstration that chemical disruption of nuclear condensate assembly weakens the insulation properties of a specific subset (∼20%) of topologically associated domain (TAD) boundaries, we report that the disrupted boundaries are characterized by a high level of transcription and striking spatial clustering. These topological boundary regions tend to be spatially associated, even interchromosomally, segregate with nuclear speckles, and harbor a specific subset of "housekeeping" genes widely expressed in diverse cell types. These observations reveal a previously unappreciated mode of genome organization mediated by conserved boundary elements harboring highly and widely expressed transcription units and associated transcriptional condensates.

Picometer-Scale Atomic Shifts Governing Subdisordered Structures in Diamond.

Diamond is considered the most promising next-generation semiconductor material due to its excellent physical characteristics. It has been more than three decades since the discovery of a special structure named n-diamond. However, despite extensive efforts, its crystallographic structure and properties are still unclear. Here, we show that subdisordered structures in diamond provide an explanation for the structural feature of n-diamond. Monocrystalline diamond with subdisordered structures is synthesized via the chemical vapor deposition method. Atomic-resolution scanning transmission electron microscopy characterizations combined with the picometer-precision peak finder technology and diffraction simulations reveal that picometer-scale shifts of atoms within cells of diamond govern the subdisordered structures. First-principles calculations indicate that the bandgap of diamond decreases rapidly with increasing shifting distance, in accordance with experimental results. These findings clarify the crystallographic structure and electronic properties of n-diamond and provide new insights into the bandgap adjustment in diamond.

Tumor cell SPTBN1 inhibits M2 polarization of macrophages by suppressing CXCL1 expression.

Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment, and the M2-type TAMs can promote tumor growth, invasion and angiogenesis, and suppress antitumor immune responses. It has been reported that spectrin beta, non-erythrocytic 1 (SPTBN1) may inhibit the infiltration of macrophages in Sptbn1+/-  mouse liver, but whether tumor SPTBN1 affects TAMs polarization remains unclear. This study investigated the effect and mechanism of tumor cell SPTBN1 on polarization and migration of TAMs in hepatoma and breast cancer. By analyzing tumor immune databases, we found a negative correlation between SPTBN1 and abundance of macrophages and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. By reverse transcription-quantitative real-time PCR assays and cell migration assays, the migration and M2 polarization of macrophages were enhanced by the culture medium from hepatocellular carcinoma cell line PLC/PRF/5, SNU449, and breast cancer cell line MDA-MB-231 with SPTBN1 suppression, which could be reversed by CXCL1 neutralizing antibody MAB275. Meanwhile, the ability of migration and colony formation of PLC/PRF/5, SNU449, and MDA-MB-231 cells were promoted when coculture with M2 macrophages. We also found that SPTBN1 regulated CXCL1 through p65 by cytoplasmic-nuclear protein isolation experiments and ChIP-qPCR. Our data suggest that tumor cell SPTBN1 inhibits migration and M2-type polarization of TAMs by reducing the expression and secretion of CXCL1 via inhibiting p65 nuclear localization.

The Role of Mitochondrial Quality Control in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity, mortality, and health care use worldwide with heterogeneous pathogenesis. Mitochondria, the powerhouses of cells responsible for oxidative phosphorylation and energy production, play essential roles in intracellular material metabolism, natural immunity, and cell death regulation. Therefore, it is crucial to address the urgent need for fine-tuning the regulation of mitochondrial quality to combat COPD effectively. Mitochondrial quality control (MQC) mainly refers to the selective removal of damaged or aging mitochondria and the generation of new mitochondria, which involves mitochondrial biogenesis, mitochondrial dynamics, mitophagy, etc. Mounting evidence suggests that mitochondrial dysfunction is a crucial contributor to the development and progression of COPD. This article mainly reviews the effects of MQC on COPD as well as their specific regulatory mechanisms. Finally, the therapeutic approaches of COPD via MQC are also illustrated.

Identification of endoplasmic reticulum stress genes in human stroke based on bioinformatics and machine learning.

After ischemic stroke (IS), secondary injury is intimately linked to endoplasmic reticulum (ER) stress and body-brain crosstalk. Nonetheless, the underlying mechanism systemic immune disorder mediated ER stress in human IS remains unknown. In this study, 32 candidate ER stress-related genes (ERSRGs) were identified by overlapping MSigDB ER stress pathway genes and DEGs. Three Key ERSRGs (ATF6, DDIT3 and ERP29) were identified using LASSO, random forest, and SVM-RFE. IS patients with different ERSRGs profile were clustered into two groups using consensus clustering and the difference between 2 group was further explored by GSVA. Through immune cell infiltration deconvolution analysis, and middle cerebral artery occlusion (MCAO) mouse scRNA analysis, we found that the expression of 3 key ERSRGs were closely related with peripheral macrophage cell ER stress in IS and this was further confirmed by RT-qPCR experiment. These ERS genes might be helpful to further accurately regulate the central nervous system and systemic immune response through ER stress and have potential application value in clinical practice in IS.

TRIB3-TRIM8 complex drives NAFLD progression by regulating HNF4α stability.

BACKGROUND & AIMS: Endoplasmic reticulum (ER) stress of hepatocytes plays a causative role in non-alcoholic fatty liver disease (NAFLD). Reduced expression of hepatic nuclear factor 4α (HNF4α) is a critical event in the pathogenesis of NAFLD and other liver diseases. Whether ER stress regulates HNF4α expression remains unknown. The aim of this study was to delineate the machinery of HNF4α protein degradation and explore a therapeutic strategy based on protecting HNF4α stability during NAFLD progression. METHODS: Correlation of HNF4α and tribbles homologue 3 (TRIB3), an ER stress sensor, was evaluated in human and mouse NAFLD tissues. RNA-sequencing, mass spectrometry analysis, co-immunoprecipitation, in vivo and in vitro ubiquitination assays were used to elucidate the mechanisms of TRIB3-mediated HNF4α degradation. Molecular docking and co-immunoprecipitation analyses were performed to identify a cell-penetrating peptide that ablates the TRIB3-HNF4α interaction. RESULTS: TRIB3 directly interacts with HNF4α and mediates ER stress-induced HNF4α degradation. TRIB3 recruits tripartite motif containing 8 (TRIM8) to form an E3 ligase complex that catalyzes K48-linked polyubiquitination of HNF4α on lysine 470. Abrogating the degradation of HNF4α attenuated the effect of TRIB3 on a diet-induced NAFLD model. Moreover, the TRIB3 gain-of-function variant p.Q84R is associated with NAFLD progression in patients, and induces lower HNF4α levels and more severe hepatic steatosis in mice. Importantly, disrupting the TRIB3-HNF4α interaction using a cell-penetrating peptide restores HNF4α levels and ameliorates NAFLD progression in mice. CONCLUSIONS: Our findings unravel the machinery of HNF4α protein degradation and indicate that targeting TRIB3-TRIM8 E3 complex-mediated HNF4α polyubiquitination may be an ideal strategy for NAFLD therapy. IMPACT AND IMPLICATIONS: Reduced expression of hepatic nuclear factor 4α (HNF4α) is a critical event in the pathogenesis of NAFLD and other liver diseases. However, the mechanism of HNF4α protein degradation remains unknown. Herein, we reveal that TRIB3-TRIM8 E3 ligase complex is responsible for HNF4α degradation during NAFLD. Inhibiting the TRIB3-HNF4α interaction effectively stabilized HNF4α protein levels and transcription factor activity in the liver and ameliorated TRIB3-mediated NAFLD progression. Our findings demonstrate that disturbing the TRIM8-TRIB3-HNF4α interaction may provide a novel approach to treat NAFLD and even other liver diseases by stabilizing the HNF4α protein.

A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion.

BACKGROUND: Structural birth defects occur in approximately 3% of live births; most such defects lack defined genetic or environmental causes. Despite advances in surgical approaches, pharmacologic prevention remains largely out of reach. METHODS: We queried worldwide databases of 20,248 families that included children with neurodevelopmental disorders and that were enriched for parental consanguinity. Approximately one third of affected children in these families presented with structural birth defects or microcephaly. We performed exome or genome sequencing of samples obtained from the children, their parents, or both to identify genes with biallelic pathogenic or likely pathogenic mutations present in more than one family. After identifying disease-causing variants, we generated two mouse models, each with a pathogenic variant "knocked in," to study mechanisms and test candidate treatments. We administered a small-molecule Wnt agonist to pregnant animals and assessed their offspring. RESULTS: We identified homozygous mutations in WLS, which encodes the Wnt ligand secretion mediator (also known as Wntless or WLS) in 10 affected persons from 5 unrelated families. (The Wnt ligand secretion mediator is essential for the secretion of all Wnt proteins.) Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects. The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis. Administration of a pharmacologic Wnt agonist partially restored embryonic development. CONCLUSIONS: Genetic variations affecting a central Wnt regulator caused syndromic structural birth defects. Results from mouse models suggest that what we have named Zaki syndrome is a potentially preventable disorder. (Funded by the National Institutes of Health and others.).

Bone-derived PDGF-BB enhances hippocampal non-specific transcytosis through microglia-endothelial crosstalk in HFD-induced metabolic syndrome.

BACKGROUND: It is well known that high-fat diet (HFD)-induced metabolic syndrome plays a crucial role in cognitive decline and brain-blood barrier (BBB) breakdown. However, whether the bone-brain axis participates in this pathological process remains unknown. Here, we report that platelet-derived growth factor-BB (PDGF-BB) secretion by preosteoclasts in the bone accelerates neuroinflammation. The expression of alkaline phosphatase (ALPL), a nonspecific transcytosis marker, was upregulated during HFD challenge. MAIN BODY: Preosteoclast-specific Pdgfb transgenic mice with high PDGF-BB concentrations in the circulation recapitulated the HFD-induced neuroinflammation and transcytosis shift. Preosteoclast-specific Pdgfb knockout mice were partially rescued from hippocampal neuroinflammation and transcytosis shifts in HFD-challenged mice. HFD-induced PDGF-BB elevation aggravated microglia-associated neuroinflammation and interleukin-1ß (IL-1ß) secretion, which increased ALPL expression and transcytosis shift through enhancing protein 1 (SP1) translocation in endothelial cells. CONCLUSION: Our findings confirm the role of bone-secreted PDGF-BB in neuroinflammation and the transcytosis shift in the hippocampal region during HFD challenge and identify a novel mechanism of microglia-endothelial crosstalk in HFD-induced metabolic syndrome.

High-Valence Metal Doping Induced Lattice Expansion for M-FeNi LDH toward Enhanced Urea Oxidation Electrocatalytic Activities.

The precise design of low-cost, efficient, and definite electrocatalysts is the key to sustainable renewable energy. The urea oxidation reaction (UOR) offers a promising alternative to the oxygen evolution reaction for energy-saving hydrogen generation. In this study, by tuning the lattice expansion, a series of M-FeNi layered double hydroxides (M-FeNi LDHs, M: Mo, Mn, V) with excellent UOR performance are synthesized. The hydrolytic transformation of Fe-MIL-88A is assisted by urea, Ni2+ and high-valence metals, to form a hollow M-FeNi LDH. Owing to the large atomic radius of the high-valence metal, lattice expansion is induced, and the electronic structure of the FeNi-LDH is regulated. Doping with high-valence metal is more favorable for the formation of the high-valence active species, NiOOH, for the UOR. Moreover, the hollow spindle structure promoted mass transport. Thus, the optimal Mo-FeNi LDH showed outstanding UOR electrocatalytic activity, with 1.32 V at 10 mA cm-2 . Remarkably, the Pt/C||Mo-FeNi LDH catalyst required a cell voltage of 1.38 V at 10 mA·cm-2 in urea-assisted water electrolysis. This study suggests a new direction for constructing nanostructures and modulating electronic structures, which is expected to ultimately lead to the development of a class of auxiliary electrocatalysts.

N-linked glycoproteins and host proteases are involved in swine acute diarrhea syndrome coronavirus entry.

IMPORTANCE: Gaining insight into the cell-entry mechanisms of swine acute diarrhea syndrome coronavirus (SADS-CoV) is critical for investigating potential cross-species infections. Here, we demonstrated that pretreatment of host cells with tunicamycin decreased SADS-CoV attachment efficiency, indicating that N-linked glycosylation of host cells was involved in SADS-CoV entry. Common N-linked sugars Neu5Gc and Neu5Ac did not interact with the SADS-CoV S1 protein, suggesting that these molecules were not involved in SADS-CoV entry. Additionally, various host proteases participated in SADS-CoV entry into diverse cells with different efficiencies. Our findings suggested that SADS-CoV may exploit multiple pathways to enter cells, providing insights into intervention strategies targeting the cell entry of this virus.

miR171-targeted SCARECROW-LIKE genes CsSCL2 and CsSCL3 regulate somatic embryogenesis in citrus.

Somatic embryogenesis (SE) is a key regeneration pathway in various biotechnology approaches to crop improvement, especially for economically important perennial woody crops like citrus. However, maintenance of SE capability has long been a challenge and becomes a bottleneck in biotechnology-facilitated plant improvement. In the embryogenic callus (EC) of citrus, we identified 2 csi-miR171c-targeted SCARECROW-LIKE genes CsSCL2 and CsSCL3 (CsSCL2/3), which exert positive feedback regulation on csi-miR171c expression. Suppression of CsSCL2 expression by RNA interference (RNAi) enhanced SE in citrus callus. A thioredoxin superfamily protein CsClot was identified as an interactive protein of CsSCL2/3. Overexpression of CsClot disturbed reactive oxygen species (ROS) homeostasis in EC and enhanced SE. Chromatin immunoprecipitation sequencing (ChIP-Seq) and RNA-Seq identified 660 genes directly suppressed by CsSCL2 that were enriched in biological processes including development-related processes, auxin signaling pathway, and cell wall organization. CsSCL2/3 bound to the promoters of regeneration-related genes, such as WUSCHEL-RELATED HOMEOBOX 2 (CsWOX2), CsWOX13, and Lateral Organ Boundaries Domain 40 (LBD40), and repressed their expression. Overall, CsSCL2/3 modulate ROS homeostasis through the interactive protein CsClot and directly suppress the expression of regeneration-related genes, thus regulating SE in citrus. We uncovered a regulatory pathway of miR171c-targeted CsSCL2/3 in SE, which shed light on the mechanism of SE and regeneration capability maintenance in citrus.

Limitations of using COX proportional hazards model in cardiovascular research.

The article by Zhao et al. titled "Associations of Triglyceride-Glucose (TyG) Index with Chest Pain Incidence and Mortality among the U.S. Population" provides valuable insights into the positive correlation between the TyG index and chest pain incidence, as well as a nonlinear relationship with mortality. However, the use of the COX proportional hazards model in their analysis presents several limitations. The assumption of constant hazard ratios over time may not hold, potentially leading to biased estimates. The model's struggle with time-dependent covariates and the possibility of residual confounding are notable concerns. Additionally, the study's subgroup analyses might suffer from reduced statistical power, and potential interactions with other metabolic markers were not explored. Considering these limitations, future research should adopt alternative approaches, such as time-varying covariate models, to provide a more comprehensive understanding of the relationship between the TyG index and cardiovascular outcomes.

Resveratrol has neuroprotective effects and plays an anti-inflammatory role through Dectin-1/p38 pathway in Aspergillus fumigatus keratitis.

PURPOSE: To determine the antifungal, anti-inflammatory and neuroprotective effects of resveratrol (RES) in Aspergillus fumigatus (A. fumigatus) keratitis. METHODS: Cytotoxicity assay and Draize eye assay were performed to assess the toxicity of RES. The antifungal effect of RES was assessed by minimal inhibitory concentration, scanning or transmission electron microscopy, propidium iodide uptake assay, and Calcofluor white staining. Phosphorylation of p38 MAPK, mRNA and protein levels of Dectin-1 and related inflammatory factors were measured by qRT-PCR, ELISA and Western blot in vitro and in vivo. Clinical score, HE staining, plate count, and myeloperoxidase test were used to observe the progress of fungal keratitis. IF staining, qRT-PCR, and the Von Frey test were selected to assess the neuroprotective effects of RES. RESULTS: RES suppressed A. fumigatus hyphae growth and altered hyphae morphology in vitro. RES decreased the expression of Dectin-1, IL-1ß and TNF-α, as well as p38 MAPK phosphorylation expression, and also decreased clinical scores, reduced inflammatory cell infiltration and neutrophil activity, and decreased fungal load. RES also protected corneal basal nerve fibers, down-regulated mechanosensitivity thresholds, and increased the mRNA levels of CGRP and TRPV-1.. CONCLUSION: These evidences revealed that RES could exert antifungal effects on A. fumigatus and ameliorate FK through suppressing the Dectin-1/p38 MAPK pathway to down-regulate IL-1ß, IL-6, etc. expression and play protective effect on corneal nerves.

Specific tissue engineering for temporomandibular joint disc perforation.

BACKGROUND: The temporomandibular joint (TMJ) disc is a critical fibrocartilaginous structure with limited regenerative capacity in the oral system. Perforation of the TMJ disc can lead to osteoarthritis and ankylosis of the TMJ because of the lack of disc protection. Clinical treatments for TMJ disc perforation, such as discectomy, hyaluronic acid injection, endoscopic surgery and high position arthroplasty of TMJ, are questionable with regard to long-term outcomes, and only three fourths of TMJ disc perforations are repairable by surgery, even in the short-term. Tissue engineering offers the potential for cure of repairable TMJ disc perforations and regeneration of unrepairable ones. OBJECTIVES: This review discusses the classification of TMJ disc perforation and defines typical TMJ disc perforation. Advancements in the engineering-based repair of TMJ disc perforation by stem cell therapy, construction of a disc-like scaffold and functionalization by offering bioactive stimuli are also summarized in the review, and the barriers developing engineering technologies need to overcome to be popularized are discussed.