MASLD, previously known as non-alcoholic fatty liver disease, has become the most prevalent chronic liver condition globally, with an estimated worldwide prevalence of approximately 38 percent based on recent systematic reviews. It ranges from simple fat accumulation to inflammation and fibrosis and can progress to cirrhosis and hepatocellular carcinoma. There are few approved pharmacological treatments, and understanding the underlying molecular drivers is a priority for researchers. Mitochondrial dysfunction has long been recognized as a central feature of MASLD. Mitochondria are the energy factories of the hepatocyte, and when they fail, fatty acids accumulate inside the cell and inflammatory damage follows. Mitophagy — the selective autophagic degradation of damaged mitochondria — is the cell’s quality control system for keeping its mitochondrial network healthy. Earlier work from other groups has shown that restoring mitophagy, for instance with quercetin or cyanidin-3-O-glucoside, can improve fatty liver disease in animal models, and that impaired mitophagy is a mechanistic biomarker in patients with the disease. But the regulatory circuits that shut mitophagy down during MASLD development have remained incompletely mapped.

The new study, led by Mei Long of the Department of Rheumatology and Immunology at the First Affiliated Hospital of Hengyang Medical School, University of South China, together with Kewei Tan of the No. 922 Hospital of the People’s Liberation Army Joint Logistics Support Force and Yujie Dong of the Department of Ultrasound Medicine at the same institution, set out to fill that gap. The researchers first profiled ZNF143, a zinc finger transcription factor that binds specific GC-rich DNA motifs and acts both as an activator and repressor of transcription. ZNF143 is best studied in cancer biology, where it promotes glioma growth through KPNA2-mediated Hippo signalling and supports breast cancer cell survival through the NQO1–p53–Beclin1 axis under metabolic stress. Prior work by the same team had already implicated ZNF143 in fatty liver disease, showing that it inhibits hepatocyte mitophagy by upregulating the long non-coding RNA NEAT1 and activating the ROCK2 pathway. The current study extends that work by identifying an entirely separate, protein-level arm of the same transcription factor’s suppressive effect on mitochondrial quality control.

To test their hypothesis, the researchers used two complementary models of MASLD. The first was an in vivo model in which C57BL/6J mice were fed a high-fat diet for 16 weeks to induce hepatic steatosis and metabolic stress. The second was an in vitro model in which Huh-7 human hepatoma cells, a standard hepatic cell line, were exposed to free fatty acids to mimic lipid overload. Histological changes were assessed by hematoxylin and eosin staining, lipid accumulation was quantified by Oil Red O staining, and mitochondrial damage was assessed with JC-1 staining to monitor mitochondrial membrane potential and transmission electron microscopy to visualize mitochondrial ultrastructure. Serum and tissue markers of liver injury, including alanine aminotransferase, aspartate aminotransferase, total cholesterol and triglycerides, were measured to gauge the severity of hepatic dysfunction.

When the team examined the high-fat-diet-fed mice and the free-fatty-acid-treated Huh-7 cells, they found that ZNF143 was significantly upregulated in both settings, consistent with a role for this transcription factor in disease progression rather than simply a bystander effect. When the researchers knocked down ZNF143 using RNA interference, the consequences were striking: lipid accumulation in the liver decreased, mitochondrial damage was reduced, and liver injury markers fell. The mechanism behind this improvement was traced to a restoration of hepatocyte mitophagy, confirming that ZNF143 acts as a brake on mitochondrial quality control during MASLD.

The next step was to identify the transcriptional target through which ZNF143 exerts its effect. Using chromatin immunoprecipitation, the researchers demonstrated that ZNF143 binds directly to the promoter region of SMURF1, a HECT-type E3 ubiquitin ligase known for its role in ubiquitinating and degrading diverse substrate proteins in cancer, vascular remodeling and inflammatory signalling. Dual-luciferase reporter assays confirmed that this binding functionally activates SMURF1 transcription. In other words, ZNF143 does not merely correlate with MASLD; it actively turns up the expression of a ubiquitin ligase that then acts downstream.

SMURF1 has a complicated history in liver biology. Previous studies have shown that deleting Smurf1 attenuates liver steatosis in mice by stabilizing p53, and that Smurf1 aggravates fatty liver disease by stabilizing SREBP-1c, a master regulator of lipid synthesis, in an E3-activity-independent manner. Conversely, another study reported that SMAD-specific E3 ubiquitin protein ligase 1 can be protective in alcoholic steatohepatitis. The current study adds a new substrate to SMURF1’s growing portfolio in hepatic disease and clarifies how this E3 ligase suppresses mitochondrial quality control. Using co-immunoprecipitation, the team showed that SMURF1 physically interacts with TRPV1, the transient receptor potential vanilloid type 1 ion channel, and that SMURF1 ubiquitinates TRPV1, leading to its proteasomal degradation. TRPV1, the receptor activated by capsaicin, the pungent compound in chili peppers, has long been linked to metabolic health. Activation of TRPV1 by dietary capsaicin improves visceral fat remodelling through calcium influx, and TRPV1 activation prevents fatty liver disease in mice through upregulation of the mitochondrial uncoupling protein UCP2. By degrading TRPV1, SMURF1 removes a protective channel that supports mitochondrial and metabolic homeostasis in the hepatocyte.

The researchers then performed epistasis experiments to confirm the hierarchy of the pathway. When they knocked down TRPV1 in free-fatty-acid-treated Huh-7 cells that had already had ZNF143 depleted, the beneficial effect of ZNF143 knockdown on mitophagy was reversed. Similarly, overexpressing SMURF1 in ZNF143-depleted cells abolished the improvement in mitochondrial clearance. These results established that ZNF143 acts upstream of SMURF1 and TRPV1 in the same linear pathway: ZNF143 turns on SMURF1 transcription, SMURF1 ubiquitinates TRPV1 and targets it for degradation, and loss of TRPV1 suppresses mitophagy, leading to mitochondrial dysfunction and fat accumulation.

The significance of the finding is twofold. First, it adds to the emerging view that MASLD is fundamentally a disorder of impaired mitochondrial turnover, not simply one of excessive lipid synthesis. Multiple groups have shown that PINK1/Parkin-mediated mitophagy relieves fatty liver disease and that reversing Parkin-related mitophagy attenuates the condition. The current work identifies ZNF143 as a transcriptional switch that turns this quality control system off, providing a mechanistic explanation for why mitophagy declines during disease progression. Second, the study places TRPV1 — a channel best known from pain biology and dietary capsaicin research — at the centre of hepatic mitochondrial homeostasis. Recent work has implicated TRPV1 in mitophagy regulation in other contexts as well, including a 2025 report showing that TRPV1 inhibits both ferroptosis and mitophagy in heart failure through SFXN2, and a 2020 study showing that blocking TRPV1 promotes terminal mitophagy in multiple myeloma. The context-dependent role of TRPV1 in mitophagy across different tissues remains an open question, but the current study firmly establishes it as a downstream effector of ZNF143 in hepatocytes.

Therapeutically, the pathway offers several potential points of intervention. Small-molecule inhibitors of ZNF143 activity have already been developed for cancer applications, including YPC-21661 and YPC-22026, which were shown to inhibit ZNF143 activity both in vitro and in vivo. Inhibitors of SMURF1 have been designed for pulmonary arterial hypertension, suggesting that pharmacological tools against this E3 ligase could be repurposed for metabolic liver disease. Alternatively, TRPV1 agonists such as capsaicin or its analogues could theoretically compensate for the loss of TRPV1 protein caused by SMURF1-mediated degradation, consistent with epidemiological and experimental data suggesting that capsaicin may promote vascular and metabolic health. The authors note that the study’s findings, generated in mice and in a human hepatoma cell line, will need to be validated in human tissue samples and in additional model systems before any clinical translation.

The research was performed in accordance with guidelines approved by the Medical Ethics Committee of the First Affiliated Hospital of University of South China, and all authors declare no conflict of interest. The datasets generated and analysed during the study are available within the published article. As global rates of MASLD continue to climb in parallel with obesity and type 2 diabetes, identifying transcription factors such as ZNF143 that govern mitochondrial quality control provides a mechanistic framework for understanding disease progression and offers a roadmap for developing targeted therapies that restore the hepatocyte’s ability to clear its damaged mitochondria before steatosis spirals into inflammation, fibrosis and cancer.

Gastric cancer remains a leading cause of cancer-related mortality worldwide, primarily due to late diagnosis and the robust resistance of tumor cells to conventional chemotherapy regimens. The discovery that the suppression of ferroptosis is instrumental in fostering this chemoresistance introduces a paradigm shift in our understanding of tumor survival strategies. Ferroptosis, distinct from apoptosis and necrosis, involves the accumulation of lethal lipid peroxides in the presence of iron, instigating selective cancer cell death. Therefore, the manipulation of the ferroptotic pathway represents a promising strategy to sensitize cancer cells to treatment.

Central to this newly elucidated mechanism is the interplay between two proteins, USP29 and SMURF1, which modulate the activity of FSP1 (ferroptosis suppressor protein 1). FSP1 functions as a guardian against ferroptosis by reducing ubiquinone to ubiquinol, preventing the buildup of lipid peroxides in cell membranes. The study reveals that USP29, a ubiquitin-specific protease, and SMURF1, an E3 ubiquitin ligase, orchestrate precise post-translational modifications that stabilize and regulate FSP1 activity, thereby suppressing ferroptosis in gastric cancer cells.

Delving deeper into the molecular intricacies, USP29 acts by deubiquitinating FSP1, counteracting the ubiquitination tag that marks proteins for proteasomal degradation. Meanwhile, SMURF1 paradoxically contributes to the fine-tuned ubiquitination dynamics that control FSP1 turnover but ensures its optimal function in ferroptosis suppression. This nuanced regulatory crosstalk preserves FSP1 levels at a threshold that is sufficient to inhibit ferroptosis without triggering proteotoxic stress, allowing cancer cells to survive cytotoxic insults from chemotherapy.

The researchers utilized a combination of advanced molecular biology techniques including co-immunoprecipitation, site-directed mutagenesis, and ubiquitination assays to decode this regulatory network. Their data demonstrated that disrupting the USP29-SMURF1-FSP1 axis sensitized gastric cancer cells to ferroptosis inducers and conventional chemoagents, dramatically decreasing cell viability. Furthermore, in vivo models reinforced these findings, where targeted inhibition of USP29 or SMURF1 resulted in tumor regression and enhanced chemotherapy efficacy.

This surge in ferroptosis upon inhibition was accompanied by an increase in iron-dependent reactive oxygen species (ROS) and pronounced lipid peroxidation, hallmark features of ferroptotic cell death. By contrast, overexpression of USP29 or SMURF1 impeded these processes, reinforcing the concept that this axis is a master regulator of ferroptosis resistance in gastric cancer. Importantly, patient-derived tumor samples exhibited elevated levels of USP29 and SMURF1, correlating with poorer prognosis and reduced response to chemotherapy, suggesting direct clinical relevance.

The implications of these findings extend beyond simple mechanistic insights. Targeting the USP29-SMURF1-FSP1 axis heralds the emergence of a novel class of therapeutic interventions aiming to-reactivate ferroptosis in resistant cancers. Current treatment modalities rarely consider ferroptosis as a therapeutic target, but this research underscores the necessity to integrate ferroptosis modulation into future precision oncology protocols, particularly for refractory gastric cancers.

Moreover, the study sparks a broader inquiry into the ubiquitin-proteasome system’s role in cancer biology, specifically how the delicate balance of ubiquitination and deubiquitination shapes tumor cell fate. Expanding this knowledge could facilitate the development of small-molecule inhibitors or RNA-based therapeutics to selectively disrupt USP29 or SMURF1 functionality, enhancing ferroptosis induction without compromising normal cellular processes.

While ferroptosis has attracted significant attention in recent years, the comprehensive understanding of its regulatory pathways in diverse cancer types remains incomplete. This research is exemplary in illuminating a critical control node within gastric cancer cells and providing a blueprint for similar investigations in other malignancies where ferroptosis resistance is a barrier to effective treatment.

Critically, the study also underscores the evolutionary conservation of this molecular machinery, as analogous pathways have been observed in other cancer models, implying that the USP29-SMURF1-FSP1 regulatory axis might represent a universal mechanism of chemoresistance beyond gastric cancer. This universality enhances the potential impact of therapeutic agents targeting this axis.

The exploration of ferroptosis modulators is no longer an abstract research objective but a tangible pathway to improved clinical outcomes. The ability to sensitize resistant tumors to existing chemotherapies by reinstating ferroptotic cell death holds promise for patients who have exhausted standard treatments. The study by Wu and colleagues thereby catalyzes the translation of ferroptosis research from bench to bedside.

Future research will need to prioritize the identification of drug candidates that can specifically impede USP29 or SMURF1 without invoking off-target effects. Additionally, combinatorial strategies employing ferroptosis inducers alongside immunotherapies or targeted agents could surmount tumor heterogeneity and adaptive resistance mechanisms.

This landmark article not only enriches our molecular understanding of gastric cancer chemoresistance but also challenges the oncology community to rethink lethal pathways as allies in cancer eradication. Ferroptosis, once an obscure form of cell death, emerges at the forefront of cancer biology as a powerful lever capable of tipping the balance toward therapeutic success.

In conclusion, the mechanistic dissection of how USP29 and SMURF1 collaboratively sustain FSP1-mediated ferroptosis suppression equips researchers and clinicians with key molecular targets to overcome chemoresistance. As new therapies emerge from these insights, the grim prognosis historically associated with gastric cancer may be decisively altered, heralding a new era in cancer treatment grounded in molecular precision and innovative cell death pathways.

Subject of Research: Gastric cancer chemoresistance; ferroptosis suppression mechanisms involving USP29, SMURF1, and FSP1.

Article Title: USP29 and SMURF1 orchestrate FSP1-mediated ferroptosis suppression to facilitate chemoresistance in gastric cancer.

Article References:
Wu, Z., Tu, X., Zhu, S. et al. USP29 and SMURF1 orchestrate FSP1-mediated ferroptosis suppression to facilitate chemoresistance in gastric cancer. Nat Commun (2025). https://doi.org/10.1038/s41467-025-66319-1

Image Credits: AI Generated