Hepatic insulin resistance, a metabolic defect that can emerge years before type 2 diabetes, has been linked to a previously underappreciated enzyme that may disrupt the liver’s ability to respond to insulin. In a study published in the International Journal of Obesity on 12 August 2026, researchers led by Ding, Jiang, Zou and colleagues identify cathepsin D, or CTSD, as a potential driver of impaired hepatic insulin action. Their findings build on earlier observations that plasma CTSD activity rises in parallel with the severity of hepatic insulin resistance in people with obesity. The new work proposes a molecular explanation for that association and suggests that blocking CTSD could help prevent the progression from metabolic dysfunction to prediabetes.
The liver is central to glucose control. During fasting, it releases glucose into the bloodstream by breaking down glycogen and generating new glucose through gluconeogenesis. After a meal, insulin normally signals the liver to reduce these processes, preventing blood glucose from rising excessively. When the liver becomes resistant to insulin, this suppression weakens. Glucose production remains inappropriately high, contributing to elevated blood glucose and placing additional stress on pancreatic beta cells, which must produce more insulin to compensate. Because hepatic insulin resistance often appears before overt hyperglycemia, understanding its earliest molecular triggers could provide a valuable opportunity for intervention.
CTSD is a lysosomal aspartic protease, an enzyme best known for breaking down proteins inside cellular compartments involved in degradation and recycling. Lysosomal enzymes are increasingly recognized as active participants in metabolic signaling, inflammation and tissue remodeling rather than passive components of cellular waste disposal. CTSD can also influence extracellular and intracellular signaling environments when its activity, localization or release changes. In obesity, altered lipid handling, chronic low-grade inflammation and cellular stress may all affect lysosomal function. The researchers’ focus on CTSD therefore places the enzyme at the intersection of metabolism and signaling, where abnormal proteolytic activity could interfere with the pathways that allow insulin to regulate liver glucose production.
The study describes a mechanism centered on what it calls “IL2RG–JAK2 signal hijacking.” IL2RG is the common gamma chain, a receptor component shared by several cytokine receptors. JAK2 is a Janus kinase, an intracellular enzyme that transmits signals from activated receptors to downstream proteins, including members of the STAT transcription-factor family. Under normal conditions, insulin signaling in hepatocytes relies principally on the insulin receptor, insulin receptor substrates and the PI3K–AKT pathway. This cascade promotes metabolic actions such as suppression of gluconeogenic gene expression. The proposed mechanism suggests that CTSD disrupts this orderly architecture by redirecting or commandeering IL2RG-associated JAK2 signaling, creating an inappropriate signaling state that undermines insulin’s metabolic message.
Such “signal hijacking” does not necessarily mean that insulin disappears or that its receptor becomes completely inactive. Insulin resistance can arise when competing pathways alter the balance, timing or cellular location of signaling events. If CTSD-driven activity engages JAK2 through IL2RG, the resulting signals may interfere with the insulin receptor network or activate transcriptional programs that oppose insulin’s effects. In hepatocytes, that could leave genes supporting glucose production insufficiently suppressed even when insulin is present. The consequence would be a liver that continues releasing glucose during conditions when it should be switching into storage and utilization mode. This type of pathway interference offers a possible explanation for how inflammation-related signaling and metabolic insulin resistance become biologically connected.
The researchers present their findings as mechanism-grounded evidence that CTSD is not merely a marker associated with hepatic insulin resistance but a functional participant in the process. Their conclusions are based on the relationship between CTSD activity and insulin resistance described in people with obesity, together with experimental investigation of the CTSD-linked signaling pathway. The study’s central claim is that manipulating CTSD can alter the molecular events associated with impaired hepatic insulin action and that targeting the enzyme can prevent features of prediabetic glucose dysregulation. The work therefore shifts attention from downstream blood-glucose abnormalities toward an upstream protease that may help initiate or amplify the defect.
The therapeutic implications are potentially significant, although they remain dependent on further validation. A CTSD-directed treatment could, in principle, interrupt the abnormal connection between lysosomal proteolysis and cytokine-associated JAK2 signaling while preserving the normal functions of insulin. Such an approach might complement established strategies that improve insulin sensitivity through weight reduction, physical activity or drugs acting on glucose metabolism. However, CTSD performs essential functions in protein degradation and cellular maintenance, meaning that systemic inhibition could carry risks. Any future drug would need to distinguish disease-promoting CTSD activity from the enzyme’s normal physiological roles, perhaps by targeting its activation, release, tissue distribution or interaction with the IL2RG–JAK2 axis rather than eliminating its activity throughout the body.
The findings also raise questions about how CTSD activity is regulated in obesity and whether it can be used to identify individuals at particularly high risk of developing prediabetes. Plasma CTSD activity may eventually serve as a biomarker of metabolic stress, but correlation alone cannot establish whether it predicts disease independently of body weight, inflammation, liver fat or other clinical variables. It will be important to determine whether CTSD activity changes before measurable hepatic insulin resistance, whether it falls when metabolic health improves, and whether genetic or pharmacological modulation of CTSD produces consistent benefits across different populations. Researchers will also need to clarify whether the proposed pathway operates similarly in human liver tissue, animal models and cultured hepatocytes.
By connecting CTSD to IL2RG–JAK2 signaling, the study offers a new way to view the early stages of glucose dysregulation: not simply as a failure of insulin production or receptor responsiveness, but as a breakdown in communication between metabolic and immune signaling systems. The liver’s response to insulin depends on precise coordination among receptor pathways, intracellular kinases, transcription factors and cellular quality-control machinery. CTSD may become important when that coordination is disturbed by obesity-related stress. If independent studies confirm that the enzyme drives rather than merely accompanies hepatic insulin resistance, CTSD could become both a mechanistic biomarker and a therapeutic target. For now, the work provides a compelling molecular lead in the search for interventions that stop prediabetes before persistent hyperglycemia takes hold.
Subject of Research: Cathepsin D’s role in hepatic insulin resistance, IL2RG–JAK2 signaling disruption, impaired glucose homeostasis, and prevention of prediabetes.
Article Title: Cathepsin D-driven IL2RG–JAK2 signal hijacking disrupts hepatic insulin action: mechanism-grounded proof that targeting cathepsin D prevents prediabetes.
Article References: Ding, L., Jiang, P., Zou, Y. et al. “Cathepsin D-driven IL2RG–JAK2 signal hijacking disrupts hepatic insulin action: mechanism-grounded proof that targeting cathepsin D prevents prediabetes.” International Journal of Obesity (2026). https://doi.org/10.1038/s41366-026-02193-1
Image Credits: AI Generated
DOI: 10.1038/s41366-026-02193-1
Keywords: Cathepsin D, hepatic insulin resistance, prediabetes, glucose homeostasis, IL2RG, JAK2, insulin signaling, obesity, liver metabolism, diabetes prevention.
