The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics of NNC0581-0001 in participants with hepatic steatosis and suspected steatohepatitis (increased liver fat and suspected inflammation). NNC0581-0001 will be given in 2 different dose levels as injection under the skin (once per month for 3 months). Participants will either get NNC0581-001 or Placebo (dummy treatment). Which treatment participants get is decided by chance. NNC0581-0001 is a new medicine which cannot be prescribed by doctors. The study will last about 58 weeks.

Inclusion Criteria:

• Considered eligible based on the medical history, physical examination, and the results of vital signs, electrocardiogram and clinical laboratory tests performed during the screening visit, as judged by the investigator.
• Male or female (of non-childbearing potential) aged 18-69 years (both inclusive) at the time of signing the informed consent.
• Body mass index (BMI) greater than or equal to (>=) 25.0 at screening.
• Liver fat content measured by magnetic resonance imaging - estimated proton density fat fraction (MRI-PDFF) >= 10 percent at screening.

Additional inclusion criteria for participants in the open-label liver biopsy cohort apply:

• Alanine aminotransferase (ALT) in men greater than (>) 30 units per liter (U/L), women > 19 U/L
• Liverstiffness, measured by FibroScan® (VCTE) > 8 kPa and less than (<) 12 kPa
• Informed consent obtained at screening for a liver biopsy to be performed at baseline and post-treatment.

Note: Participants with confirmed metabolic dysfunction-associated steatohepatitis (MASH), based on a prior liver biopsy, can be included in the open-label cohort.

Exclusion Criteria:

• Any disorder, which in the investigator's opinion might jeopardise participant's safety or compliance with the protocol.
• Any laboratory safety parameter, at screening, outside the extended laboratory ranges, and considered clinically significant per the principal investigator (see laboratory provided reference ranges for specific values). Of note, re-screening or re-sampling is NOT allowed if the individual has failed one of the exclusion criteria related to the following laboratory parameters:
• ALT >= 3 × upper limit of normal (ULN)
• Aspartate aminotransferase (AST) >= 3 × ULN
• Bilirubin > 1.5 × ULN
• Estimated glomerular filtration rate (eGFR) < 50 milliliter per minute per 1.73 square meters (mL/min/1.73 m^2) at screening.

Additional exclusion criteria for participants in the open-label liver biopsy group apply:

• Medical history of abnormal bleeding
• BMI > 34.9 kilograms per square meters (kg/m^2)
• Presence of ascites
• Cirrhosis based on screening tests or historical biopsy
• Lab abnormalities of platelets count < 150 × 10^9 per liter or International Normalized Ratio (INR) > 1.2
• Concomitant use of medication:
• anticoagulants or herbal supplements with an anticoagulative effect (as judged by the principal investigator)
• antiplatelet medications
• exception for aspirin that must be stopped 5 days prior to procedure and Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) that must not be taken within 3 days of the procedure.

According to the Novo Nordisk disclosure commitment on novonordisk-trials.com.

Sponsor staff involved in the clinical trial is masked according to company standard procedures.