USP7, historically known as HAUSP because it was first identified through its interaction with the herpes simplex virus type 1 protein ICP0, is a cysteine protease whose catalytic activity is modulated by a large N-terminal TRAF domain. This domain is the molecular handshake that allows USP7 to recognize a remarkably diverse cast of substrate proteins. By removing ubiquitin marks from these partners, USP7 can stabilize them, alter their localization, or change their activity, and in doing so it touches nearly every major process a cancer cell cares about: DNA damage repair, epigenetic programming, cell cycle control, apoptosis, metabolism and immune evasion. The stakes are high well beyond oncology. The review emphasizes that USP7 is indispensable for normal physiology, since mice engineered to lack the enzyme from conception die during early embryonic development, a finding that underscores its essential role in maintaining genome stability and developmental homeostasis.

The most famous thread in the USP7 story runs through the tumor suppressor p53, the guardian of the genome whose loss or mutation underpins roughly half of all human cancers. Under ordinary, unstressed conditions in tumors that still carry a functional, wild-type copy of the p53 gene, USP7 tends to act as a quiet accomplice of cancer. Its preferred client in this setting is MDM2, the E3 ubiquitin ligase whose entire job is to attach ubiquitin to p53 and drag it to the proteasome. By keeping MDM2 stable and active, USP7 accelerates p53 turnover and keeps the tumor suppressor’s alarm system dialed down, allowing malignant cells to proliferate unchecked. In this scenario, inhibiting USP7 would seem like an obvious win: MDM2 degrades, p53 accumulates, and the cell either arrests its cell cycle or initiates apoptosis.

Yet the biology refuses to stay simple. The review details how, under conditions of DNA damage stress, USP7 can flip sides entirely. When the genome is injured, USP7 can directly deubiquitinate p53 itself, stabilizing the tumor suppressor and helping it trigger the transcriptional programs that halt division and repair the damage. This context-dependent duality, the authors argue, is the central paradox that has complicated every attempt to drug the enzyme. In a p53 wild-type tumor, a USP7 inhibitor might unleash p53 and kill the cancer, but in normal tissues exposed to genotoxic stress from chemotherapy or radiation, the same inhibition could blunt a protective p53 response. The enzyme is, in the review’s framing, a double-edged sword whose effect depends on which substrates are present, what stress the cell is under, and what the p53 status happens to be.

In tumors where p53 is mutated or deleted altogether, the calculus changes again. With the p53 checkpoint gone, USP7’s oncogenic contributions come almost entirely from its other clients, and the review catalogs an impressive roster. USP7 stabilizes the transcription factor Myc, a master driver of proliferation whose overexpression marks many aggressive malignancies. It stabilizes NF-κB components, fueling inflammatory signaling and survival. It protects EZH2, the catalytic engine of the Polycomb Repressive Complex 2, which deposits the repressive H3K27me3 histone mark and silences tumor suppressor programs. Through these and other substrates, USP7 supports metabolic reprogramming, including the glycolytic shift mediated by proteins such as SLC2A1, hexokinase 2 and lactate dehydrogenase A, and it helps cancer cells dodge immune surveillance, in part through effects on PD-L1 and other immune-modulatory molecules.

The enzyme’s reach extends deep into the DNA damage response, a dimension that carries direct therapeutic implications. USP7 interacts with and stabilizes components of the checkpoint machinery, including the MRN complex mediator MDC1, the p53-binding protein 53BP1, checkpoint kinase 1 and its partner claspin, as well as repair factors such as CtIP and the nuclease SAMHD1. By keeping these proteins abundant, USP7 helps cancer cells survive the constant DNA insults of rapid division and, more troublingly, helps them repair the damage inflicted by genotoxic chemotherapy and radiation. This has prompted interest in combining USP7 inhibitors with DNA-damaging agents or with PARP inhibitors, on the logic that disabling USP7 would leave tumors with fewer tools to patch their broken genomes. The review also connects USP7 to epigenetic regulation beyond EZH2, noting interactions with LSD1, HDAC1 and the DNA methyltransferases DNMT1, DNMT3A and DNMT3B, positioning the enzyme as a hub where chromatin state and genome maintenance converge.

The clinical evidence base is growing across tumor types. The review highlights roles for USP7 in T-cell acute lymphoblastic leukemia, where it supports NOTCH1-driven signaling, and in acute myeloid leukemia, as well as in activated B-cell-like diffuse large B-cell lymphoma, where USP7 inhibition has been explored in combination with B-cell receptor pathway blockade and glucocorticoids such as dexamethasone. In solid tumors, USP7 has been implicated in pancreatic ductal adenocarcinoma through interactions with IGF2BP2 and platelet-derived growth factor signaling involving cancer-associated fibroblasts, in HER2-positive breast cancer, in non-small cell lung cancer, and in hepatobiliary and other gastrointestinal malignancies. Natural products have also entered the picture, with the toad venom-derived compound cinobufagin reported to act through USP7 in preclinical models. Each of these associations reinforces the same conclusion: USP7 sits at a bottleneck through which many oncogenic signals pass.

Drug developers have responded with a wave of small-molecule inhibitors, and the review provides a technical tour of how they were built. Early compounds were identified using activity-based assays with artificial substrates such as ubiquitin-7-amino-4-methylcoumarin, and their binding was characterized by techniques including surface plasmon resonance, isothermal titration calorimetry and nuclear magnetic resonance spectroscopy. Structure-based drug design against the catalytic domain has produced increasingly potent inhibitors, some with half-maximal inhibitory concentrations in the low nanomolar range. Yet the review is candid about why none has yet transformed oncology practice. On-target toxicity remains a serious concern, a direct consequence of USP7’s essential normal functions. Selectivity is insufficient, because the catalytic domains of the more than fifty human ubiquitin-specific proteases are architecturally similar, raising the specter of off-target effects on related DUBs. Pharmacokinetic properties have often been poor, and efficacy has proved stubbornly context-dependent, working in some cellular settings and failing in others for reasons that are only partly understood.

The path forward, the authors argue, requires more than simply building stronger inhibitors. They call for the development of highly selective molecules, ideally ones that exploit the TRAF domain and substrate-recognition surfaces rather than the conserved catalytic core, which could discriminate USP7 from its relatives. They emphasize the need to elucidate context-specific regulatory networks so that clinicians can predict which patients will benefit, and they advocate the search for predictive biomarkers, with p53 status, EZH2 dependence and Myc activation emerging as obvious candidates for stratification. Combination regimens, pairing USP7 inhibitors with immune checkpoint blockade, epigenetic drugs, DNA damage response inhibitors or conventional chemotherapy, are highlighted as the most promising route to overcoming the redundancy that cancer cells exploit when a single pathway is blocked.

What makes the USP7 story resonate beyond the specialist literature is what it reveals about modern cancer biology as a whole. The ubiquitin-proteasome system, once viewed mainly as cellular housekeeping, has turned out to be a dense regulatory network in which a single deubiquitinase can simultaneously tune tumor suppression, oncogene activation, genome repair and immune recognition. USP7 embodies the promise and the peril of targeting such hubs: it is druggable, it is implicated across an extraordinary range of malignancies, and inhibiting it could reverse chemoresistance in ways that conventional targeted agents cannot. But its essential role in embryonic development and genome stability means that any clinical strategy must walk a narrow line between poisoning the tumor and harming the patient. The Hangzhou team’s synthesis makes clear that the next phase of USP7 research will be less about proving the enzyme matters and more about learning, with molecular precision, when and how to pull the trigger.

Subject of Research: The role of the deubiquitinase USP7 in tumor progression and the development of USP7-targeted cancer therapies

Article Title: Ubiquitin-specific protease 7 (USP7): a key deubiquitinase governing tumor progression and therapeutic vulnerabilities

Article References: Ubiquitin-specific protease 7 (USP7): a key deubiquitinase governing tumor progression and therapeutic vulnerabilities. (n.d.). https://doi.org/10.1186/s12935-026-04483-0

Image Credits: AI Generated

DOI: 10.1186/s12935-026-04483-0

Keywords: USP7, deubiquitinase, p53, MDM2, ubiquitin-proteasome system, small-molecule inhibitors, targeted therapy, DNA damage response, EZH2, Myc, cancer drug discovery, combination therapy

Claudin-1, or CLDN1, has long been defined by its day job. It is a tight junction protein, a structural component that seals the gaps between epithelial cells, controlling what passes through tissue barriers and holding cellular sheets together. In cancer research, CLDN1 has mostly been studied in that architectural context, with its dysregulation implicated in tumor progression and metastasis across multiple cancer types. But the new work, led by researchers at Nanjing Medical University and collaborating institutions in China, demonstrates that CLDN1 has a second, hidden life inside the cell. Far from the cell membrane’s junctions, the protein operates deep within the endoplasmic reticulum, the organelle responsible for folding and quality-controlling the proteins that cells need to survive.

The endoplasmic reticulum is an unforgiving workplace. When protein folding demands exceed the organelle’s capacity, misfolded proteins accumulate and trigger a condition called endoplasmic reticulum stress. If the stress is mild, the cell activates adaptive signaling pathways that expand folding capacity and restore balance. If the stress is severe or prolonged, the same machinery flips into a destructive mode, executing a form of programmed cell death designed to eliminate damaged cells. Chemotherapy drugs such as docetaxel impose exactly this kind of burden, overwhelming the folding machinery and pushing cancer cells toward the lethal threshold. The researchers reasoned that tumors which survive this assault must have found ways to buffer the stress, and their search for those buffers led them directly to CLDN1.

To identify the key regulators of neuroendocrine differentiation and docetaxel resistance, the team integrated transcriptome data from multiple public cohorts with their own RNA sequencing of prostate cancer models. This multi-cohort analysis pinpointed CLDN1 as a consistent feature of both neuroendocrine prostate cancer and chemotherapy-resistant tumors. The correlation was striking: in clinical tissue specimens from human prostate cancer patients, CLDN1 expression showed a significant positive relationship with established neuroendocrine markers such as neuron-specific enolase and synaptophysin. In other words, the tumors that expressed the most CLDN1 were the ones most likely to display the neuroendocrine signature that portends aggressive, treatment-resistant disease.

Having established the clinical association, the researchers moved into mechanistic territory. Using co-immunoprecipitation coupled with mass spectrometry, they mapped the proteins that physically associate with CLDN1 and discovered that it interacts with two critical players in endoplasmic reticulum biology. The first is USP7, a deubiquitinase enzyme that removes ubiquitin tags from target proteins. Ubiquitin attachment is the cell’s universal signal for destruction, so deubiquitinases act as molecular rescuers, pulling proteins back from the degradation pathway. The second player is calnexin, or CANX, a chaperone protein embedded in the endoplasmic reticulum membrane that helps newly synthesized proteins fold correctly and directs misfolded ones toward degradation.

The experiments revealed a precise biochemical sequence. CLDN1 promotes the recruitment of USP7 to the endoplasmic reticulum membrane, where USP7 removes ubiquitin molecules from calnexin at three specific conserved lysine residues, numbered K118, K170, and K199. The team confirmed this site specificity through ubiquitination assays and site-directed mutagenesis, showing that altering these lysines abolished the protective effect. With its ubiquitin tags removed, calnexin is stabilized, and the endoplasmic reticulum gains a larger and more durable folding workforce. Transmission electron microscopy provided visual confirmation of the cellular consequences, revealing that CLDN1-high cells maintained endoplasmic reticulum structure under conditions that would otherwise damage the organelle. The practical result is that chemotherapy-induced stress, which should push these cells over the lethal threshold, is instead absorbed and neutralized.

The functional consequences of this buffering system extend beyond simple survival. Using gain- and loss-of-function approaches in prostate cancer cell lines, the researchers showed that CLDN1 drives neuroendocrine transdifferentiation, pushing cells toward the lineage-plastic state that characterizes treatment-resistant disease. Conversely, depleting CLDN1 undermined both the neuroendocrine shift and resistance to docetaxel. The team validated these findings in vivo using subcutaneous xenograft models in mice, where manipulating CLDN1 levels changed how tumors responded to chemotherapy. The picture that emerges is of a single protein coordinating two of the most feared features of advanced prostate cancer: the identity change that escapes targeted therapies and the stress tolerance that escapes cytotoxic drugs.

Perhaps the most therapeutically exciting finding came when the researchers deliberately reversed the process. Tunicamycin, a pharmacological agent that blocks a key step in protein glycosylation and thereby activates endoplasmic reticulum stress, effectively reversed CLDN1-induced neuroendocrine differentiation and chemoresistance in the animal models. In essence, re-imposing the stress that CLDN1 had learned to buffer stripped the tumors of their adaptive advantage. This proof-of-concept experiment suggests that the endoplasmic reticulum stress response is not merely a bystander in treatment resistance but an actionable vulnerability. If clinicians could pharmacologically tip the stress balance in the lethal direction at the right moment, they might prevent or reverse the lineage plasticity that makes neuroendocrine prostate cancer so difficult to treat.

The study also expands the conceptual framework of cancer biology in a broader sense. Tight junction proteins have traditionally been studied as structural elements, and organelle homeostasis has traditionally been studied through dedicated stress-response pathways. The CLDN1-USP7-CANX axis demonstrates that these worlds intersect, with a junctional protein moonlighting as a regulator of deubiquitinase recruitment and chaperone stability deep inside the cell. This noncanonical function provides a molecular link between cell architecture, protein quality control, and tumor cell reprogramming, and it raises the question of whether other tight junction proteins harbor similar hidden roles in organelle biology. The finding also adds to a growing appreciation that post-translational modifications, particularly site-specific deubiquitination, can serve as master switches controlling how cancer cells respond to therapeutic pressure.

For patients with advanced prostate cancer, the clinical stakes are considerable. Neuroendocrine prostate cancer typically emerges after years of androgen receptor-targeted treatment, and once it appears, prognosis is poor because neither hormonal manipulation nor standard chemotherapy works reliably. The identification of the CLDN1-USP7-CANX pathway offers several potential intervention points: blocking the CLDN1-USP7 interaction, inhibiting USP7 recruitment to the endoplasmic reticulum, or pharmacologically exploiting the stress vulnerability that CLDN1 normally shields. USP7 inhibitors already exist in early clinical development for other indications, which could accelerate translational efforts. The work was supported by the National Natural Science Foundation of China and the Jiangsu Provincial Health Commission, and the corresponding authors include Lei Yang, Haoli Yin, and Qingyi Zhu. While the road from mechanism to medicine is long, this study provides a clear molecular target for a disease state that has stubbornly resisted every previous attempt at rational attack, and it demonstrates that sometimes the most important discoveries about a well-known protein are found in the places no one thought to look.

Subject of Research: The role of Claudin-1 in endoplasmic reticulum stress regulation, lineage plasticity, and chemoresistance in prostate cancer

Article Title: Noncanonical function of Claudin-1 mitigates lethal endoplasmic reticulum stress to drive prostate cancer lineage plasticity and chemoresistance

Article References: Li, Y., Li, Y., Li, S., Li, K., Dong, Y., Chen, Z., Zhou, K., Ji, Z., Yang, L., Yin, H., & Zhu, Q. (2026). Noncanonical function of Claudin-1 mitigates lethal endoplasmic reticulum stress to drive prostate cancer lineage plasticity and chemoresistance. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06430-8

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06430-8

Keywords: prostate cancer, Claudin-1, neuroendocrine prostate cancer, endoplasmic reticulum stress, lineage plasticity, chemoresistance, docetaxel, USP7, calnexin, deubiquitination, castration-resistant prostate cancer, tumor reprogramming