TEAD inhibitor induced switch in energy metabolism drives human podocyte injury in vitro

Our plain-English summary of TEAD inhibitor induced switch in energy metabolism drives human podocyte injury in vitro, by A. Zielinski, J. Hauptstein, B. Baier, et al (Archives of Toxicology, 2026).

The study

• Authors: A. Zielinski, J. Hauptstein, B. Baier, P. Schaarschmidt, N. Ketter, D.R. Dietrich, F. Meier
• Journal: Archives of Toxicology
• Published: 2026;100(11):5181-5194
• Read it: PubMed · Publisher · Free full text

Abstract

Early detection and understanding of the potential adverse effects of a drug candidate is of utmost importance to reduce the attrition rate during drug development while delivering safe medications to patients. The kidney is one of the most frequently challenged organs involved in drug-induced toxicity, including general glomerulopathy and podocyte- specific cytotoxicity with ensuing overt proteinuria. Whilst TEAD inhibitors address the need for treatment of mesotheliomas and other tumours unaffected by approved drugs, animal testing and clinical trials provide evidence of renal toxicity induced by this novel class of drugs. Here we present an in vitro test system consisting of immortalized human podocytes PODO/TERT256 to characterize the potential adverse effects of TEAD inhibitors. We demonstrate that TEAD inhibitors K-975, IK-930 and VT-107 affect the podocyte monolayer in a wide dose range (33.3-100 µM), disrupt the cellular vesicle system, and subsequently induce cell death, especially after exposure to pan-TEAD inhibitors (VT-107 and K-975). Of note, low micromolar concentrations of TEAD inhibitors lowered mitochondrial oxidative phosphorylation directly after exposure which was confirmed by reduced basal ATP levels after 3 d of exposure. In summary, the in vitro human podocyte model presented can characterize glomerular filtration functionality decline subsequent to TEAD inhibitor exposure and thus represents a promising model for early detection and prediction of potential drug related glomerulopathy in humans.

© 2026. The Author(s).

In plain English

This was a laboratory (in vitro) study, not a study of people or asbestos exposure. The authors used an immortalized human podocyte cell line, PODO/TERT256, to test three TEAD inhibitors (drugs being developed for mesothelioma and other tumours): IK-930, VT-107 and K-975. Confluent cell layers were exposed to up to 100 micromolar, and viability, cell death, imaging, barrier impedance, permeability to labelled dextrans, oxygen consumption, extracellular acidification and ATP were measured. After 48 hours of single exposure, VT-107 significantly reduced viability from 33.3 micromolar, K-975 only at 100 micromolar, and IK-930 caused no major toxicity at or below 100 micromolar; at 24 hours, 100 micromolar IK-930 and 33.3 micromolar K-975 significantly lowered viability, with recovery by 48 hours. All three compounds altered impedance and lowered the oxygen consumption rate, including at concentrations that were not cytotoxic; extracellular acidification rose with IK-930 and K-975, but VT-107 did not induce this compensatory increase. In a repeated-dosing experiment of which one replicate time course was displayed, non-cytotoxic 33 micromolar K-975 lowered impedance to 60% after the first treatment with almost complete recovery, while the second treatment at 48 hours lowered it to 50% with no recovery at 72 hours. Palmitic acid co-exposure did not prevent the effects on ATP or cell count.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: in vitro cell-culture (toxicology) experiment using an immortalized human podocyte line
• Who was studied: PODO/TERT256 immortalized human podocyte cells, obtained commercially and grown as monolayers; experiments at the University of Konstanz and Boehringer Ingelheim laboratories (no human or animal subjects)
• Exposure: the TEAD inhibitors IK-930 (TEAD1-selective), VT-107 and K-975 (pan-TEAD), up to 100 micromolar, in 0.25% DMSO, single or repeated dosing, with or without palmitic acid (1, 11 or 100 micromolar)
• Main results:
  • After 48 h, VT-107 was the most cytotoxic to the podocytes (significant viability loss at 33.3 micromolar); IK-930 caused no major toxicity up to 100 micromolar; K-975 reduced viability only at 100 micromolar
  • Podocytes exposed to 100 micromolar IK-930 or 33.3 micromolar K-975 showed a significant viability drop at 24 h with recovery by 48 h
  • Intracellular vesicles appeared in the podocytes within 30 minutes of exposure to all three compounds
  • K-975 at 33.3 micromolar or below lowered monolayer impedance after a single dose, with nearly complete recovery by 48 h
  • Apparent permeability of the podocyte monolayer rose for all three inhibitors at their highest concentrations, and for 70 kDa dextran also at concentrations that were not cytotoxic (100 micromolar IK-930, 33 micromolar K-975)
  • All three inhibitors produced a concentration-dependent fall in oxygen consumption rate in the podocytes
  • A compensatory rise in extracellular acidification rate followed IK-930 and K-975, whereas VT-107 did not induce it
  • With repeated dosing, non-cytotoxic 33 micromolar K-975 lowered impedance to 60% after the first treatment with almost complete recovery, and to 50% after the second treatment at 48 h with no recovery at 72 h
  • The displayed impedance time course for repeated dosing came from one independent experiment with three technical replicates
  • Co-exposure to palmitic acid with 11.1 micromolar VT-107 did not alter ATP level, cell count or impedance at 72 h; palmitic acid had no effect with 11.1 micromolar K-975
• The authors' conclusion: The authors concluded that this human podocyte in vitro model can characterize decline in glomerular filtration function after TEAD inhibitor exposure and may serve for early detection and prediction of potential drug-related glomerulopathy in humans, and that the system revealed immediate inhibition of mitochondrial function
• Limitations the authors state:
  • The authors stated that whether vesicles sequestered crystallized or aggregated inhibitor could only be confirmed by analysing vesicle contents, which was not done
  • The authors presented the explanation of the immediate metabolic effect as a hypothesis of a possible off-target effect, not a demonstrated mechanism

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Clinical Trial.

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