Journal Article

DKFZ-2025-02370

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Diclofenac and acetaminophen dim the acute-phase response but amplify expression of the iron regulator hepcidin in liver cancer cells.

Zeilfelder, A. (First author)DKFZ* ; Vanlier, J. ; Mölders, C.DKFZ* ; Kastl, P.DKFZ* ; Helm, B.DKFZ* ; Burbano de Lara, S.DKFZ* ; Möcklinghoff, T.DKFZ* ; Leonidou, N.DKFZ* ; Holstein, E.DKFZ* ; Vlasov, A.DKFZ* ; Held, A.DKFZ* ; Wilken, S.DKFZ* ; Hoffmann, K. ; Schicht, G. ; Scheffschick, A. ; Katerinopoulou, M. ; Giehl-Brown, E. ; Kahlert, C. ; Michalski, C. ; Seehofer, D. ; Damm, G. ; Muckenthaler, M. U. ; Schilling, M.DKFZ* ; Timmer, J. ; Klingmüller, U. (Last author)DKFZ*

2025
Elsevier Maryland Heights, MO

Abstract: 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.

Keyword(s): anemia ; bone morphogenetic protein signaling ; drug-induced liver injury ; hepcidin ; inflammation ; interleukin-6 ; liver cancer ; mathematical modeling ; proteomics

Note: #EA:B200#LA:B200# / 2025 Nov 19;16(11):101431

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Contributing Institute(s):

1. B200 Systembiologie der Signaltransduktion (B200)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2025

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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