The Innovation

CureDiab addresses MASLD with a novel first-in-class therapy. Positive allosteric modulators of the GABA-A receptor are able to counteract lipotoxic damage of hepatocytes and dual-target hepatic stellate cells to reduce fibrosis. Thus, activation of this pathway protects hepatocytes at an early stage and hepatic stellate cells at a more severe stage. Therefore, these molecules are exceptional candidates for combination therapy.

A Dual Action Profile:

Protective Effect on Injured Hepatocytes & Direct Anti-Fibrotic Action on Stellate Cells

Our thioacrylamide compounds (positive allosteric modulators (PAM) of the GABA-A receptor) showed hepatoprotective and also anti-fibrotic effects in liver injury, displaying attractive therapeutic targets for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). The Figure below shows the most prominent findings in different MASLD models that highlight different pathophysiologies. Created with

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1) Hepatocyte Protection
Exposure to GABA has been proposed to exert a hepatoprotective effect in liver toxicity both in vivo and in vitro [1-3]. We can confirm a protective function in hepatocyte injury with our GABA PAMs. The GABA-A receptor is a pentameric Cl- channel, composed of different combinations of subunits: α(1–6), β(1–3), γ(1–3), δ, ε, θ, π and ρ(1–3). Our PAMs are small molecules, devoid of blood brain barrier penetration and binding at an allosteric binding site. We proofed its selective modulator activity by patch clamping, calcium influx measurements and assays with the non-competitive GABA-A channel blocker picrotoxin.
The promising anti-apoptotic effect was demonstrated by reduced caspase 3/7 activity, cleaved caspase 7-protein expression and TUNEL assay in hepatocytes [4]. The PAM reduces lipotoxic-induced apoptosis in hepatocytes by preventing inflammation, DNA damage and ER stress [5]. Since cell death, including apoptosis, is a critical step in the progression of MASLD, PAMs of the GABA-A receptor may arise as an innovative pharmacological tool to treat or prevent MASLD as a first-in-class drug.
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TUNEL-staining of our lipotoxicity model and the protective impact of HK4: DNA fragmentation, a signal of apoptosis, was assessed by TUNEL-staining in HepG2 cells after 24h of lipotoxicity treatment. Representative images of TUNEL-positive stained cells (red), while nuclei were counterstained with Hoechst (blue). Palmitate (PA), Staurosporine (STP)

2) Anti-fibrotic Action on Hepatic Stellate Cells
Our lead compound HK3 further demonstrated its dual targeting ability by attenuating the secretion of inflammation-related biomarkers and preventing the upregulation of pro-fibrotic markers. These markers play a pivotal role in driving the fibrotic process, and their suppression is a significant step toward halting liver fibrosis. Transcriptomic analysis supported the anti-fibrotic effects of HK3, as they reversed the gene expression pattern of activated stellate cells to resemble that of quiescent ones.
Moreover in vivo data confirmed the beneficial effects of our lead compound HK3. In a CCl4-intoxicated mouse model, HK3 reduced the hepatic fibrosis score and liver collagen deposition.
In addition, HK3 decreased intracellular lipid levels, suppressed the release of pro-inflammatory cytokines, and lowered pro-collagen concentration in a 3D spheroid system derived from human MASH cells.

A step towards curing MASLD !


1. Norikura T, Kojima-Yuasa A, Opare Kennedy D, Matsui-Yuasa I. Protective effect of gamma-aminobutyric acid (GABA) against cytotoxicity of ethanol in isolated rat hepatocytes involves modulations in cellular polyamine levels. Amino Acids. 2007;32(3):419-423. https://doi:10.1007/s00726-006-0381-3.

2. Hata T, Rehman F, Hori T, Nguyen JH. GABA, γ-Aminobutyric Acid, Protects Against Severe Liver Injury. J Surg Res. 2019;236:172-183. https://doi:10.1016/j.jss.2018.11.047.

3. Shilpa J, Roshni BT, Chinthu R, Paulose CS. Role of GABA and serotonin coupled chitosan nanoparticles in enhanced hepato-cyte proliferation. J Mater Sci: Mater Med. 2012;23(12):2913-2921. https://doi:10.1007/s10856-012-4754-8.

4. Rohbeck, Elisabeth; Hasse, Birgit; Koopmans, Guido; Romero, Alejandra; Belgardt, Bengt-Frederik; Roden, Michael et al. (2022): Positive allosteric γ-aminobutyric acid type A receptor modulation prevents lipotoxicity-induced injury in hepatocytes in vitro. In: Diabetes, obesity & metabolism 24 (8), S. 1498–1508. DOI: 10.1111/dom.14719.

5. Rohbeck, Elisabeth; Niersmann, Corinna; Köhrer, Karl; Wachtmeister, Thorsten; Roden, Michael; Eckel, Jürgen; Romacho, Tania (2023): Positive allosteric GABAA receptor modulation counteracts lipotoxicity-induced gene expression changes in hepatocytes in vitro. In: Frontiers in physiology 14, S. 1106075. DOI: 10.3389/fphys.2023.1106075.