Diclofenac and acetaminophen dim the acute-phase response but amplify expression of the iron regulator hepcidin in liver cancer cells
Cancer patients frequently suffer from anemia and cancer-related pain, which can be treated by non-opioid analgesics such as diclofenac (DCF) and acetaminophen (APAP) attenuating inflammatory responses. The pro-inflammatory cytokine interleukin (IL)-6 triggers the expression of acute-phase proteins, including the iron regulator hepcidin. Using proteomics and dynamic pathway modeling, we show that DCF and APAP directly impact IL-6 signaling by enhancing the induction of the feedback-inhibitor suppressor of cytokine signaling 3 (SOCS3), reducing signal transducer and activator of transcription (STAT)3 phosphorylation, and decreasing the expression of most acute-phase proteins except for hepcidin. In primary human hepatocytes (PHHs), the impact depends on the patient-specific extent of SOCS3 induction, which is anti-correlated with hepcidin expression. Whereas, in liver cancer cells, DCF and APAP stabilize the interaction of autocrine secreted bone morphogenic protein (BMP) with its receptor, resulting in strongly amplified hepcidin expression. Our studies suggest that co-inhibition of the BMP receptor counteracts excessive hepcidin production upon treatment with pain-relieving drugs and could prevent iron-deficiency-caused anemia in liver cancer. A record of this paper's transparent peer review process is included in the supplemental information.
Authors
- Artyom Vlasov
- Gerda Schicht (ORCID: https://orcid.org/0000-0002-2799-6210)
- Andrea Scheffschick (ORCID: https://orcid.org/0000-0002-2848-2617)
- Daniel Seehofer (ORCID: https://orcid.org/0000-0002-7492-8309)
- Sebastian Burbano de Lara (ORCID: https://orcid.org/0000-0002-5364-2686)
- Christina Mölders (ORCID: https://orcid.org/0000-0002-9875-2088)
- Jens Timmer (ORCID: https://orcid.org/0000-0003-4517-1383)
- Nantia Leonidou (ORCID: https://orcid.org/0000-0002-0248-6679)
- Christoph Kahlert (ORCID: https://orcid.org/0000-0003-4124-7918)
- Martina U. Muckenthaler
- Ursula Klingmüller (ORCID: https://orcid.org/0000-0001-9845-3099)
- Georg Damm (ORCID: https://orcid.org/0000-0002-2104-8076)
- Philipp Kastl (ORCID: https://orcid.org/0009-0000-7561-4312)
- Esther Giehl-Brown (ORCID: https://orcid.org/0000-0003-2216-0358)
- Marcel Schilling (ORCID: https://orcid.org/0000-0002-9517-5166)
- Katrin Hoffmann (ORCID: https://orcid.org/0000-0003-0393-1532)
- Christoph Michalski (ORCID: https://orcid.org/0000-0003-3520-1040)
- Silvana Wilken
- Till Möcklinghoff
- Barbara Helm (ORCID: https://orcid.org/0000-0002-8817-2979)
- Joep Vanlier
- Arthur-Jean Held
- Elisa Holstein
- Markella Katerinopoulou
- Anja Zeilfelder
Institutions
- University of Freiburg (DE)
- German Cancer Research Center (DE)
- Heidelberg University (DE)
- University Hospital Heidelberg (DE)
- University Hospital Leipzig (DE)
- Heidelberg Engineering (Germany) (DE)
- German Center for Lung Research (DE)
Publication Details
- Journal
- Cell Systems
- Published
- 2025-11-01
- DOI
- https://doi.org/10.1016/j.cels.2025.101431
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 0.00